TAP Vol 4 Issue 5 by Harborside Press LLC

Pomalidomide in Multiple Myeloma

| New Strategies for Pancreatic Cancer

| ASCO State Affiliates

108

VOLUME 4, ISSUE 5

MARCH 15, 2013

Editor-in-Chief, James O. Armitage, MD

Gastrointestinal Cancers Symposium

Bevacizumab plus Capecitabine Has Robust Effect in Elderly Patients with Colorectal Cancer

ASCOPost.com

Cancer Has Made Me A Better Doctor

By Caroline Helwick

n elderly patients with treatment-naive metastatic colorectal cancer, a trend toward a survival benefit was observed for bevacizumab (Avastin) plus capecitabine (Xeloda) in the international phase III AVEX trial, which was presented at David Cunningham, MD the 2013 Gastrointestinal Cancers Symposium by David Cunningham, MD, Consultant Medical Oncologist and Head of the Gastrointestinal Unit at the Royal Marsden Hospital, London.1 Although bevacizumab is a standard of care in metastatic colorectal cancer, AVEX is the first phase III trial to prospectively evaluate the use of the drug—or any biologic—in an elderly colorectal cancer popu-

lation, “a population that is in general undertreated,” Dr. Cunningham said. The study enrolled 280 treatment-naive patients aged ≥ 70 (mean age 76) across 10 countries. As firstline treatment for metastatic disease, patients were randomly assigned to receive 7.5 mg/kg bevacizumab every 3 weeks and 1,000 mg/m2 capecitabine twice a day on days 1 to 14, or 1,000 mg/m2 capecitabine alone twice a day on days 1 to 14. The addition of bevacizumab to capecitabine significantly improved progression-free and overall survival. Progression-free survival was 9.1 months with the combination vs 5.1 months without (HR = 0.53; P < .001), which was consistent across all subgroups. continued on page 23

continued on page 29

Building CancerLinQ: The Road to Faster, More Efficient Treatment Delivery By Jo Cavallo

development and eventual deployment of ASCO’s breast cancer–specific prototype for CancerLinQ. (See “ASCO’s Approach to Health Information Technology and the Rapid-learning System,” in the January 15 issue of The ASCO Post.) Recently, The ASCO Post talked with Dr. Hudis about CancerLinQ.

There really is no limit to the kinds of medical information that might be included to allow ever more precise feedback and guidance in the form of clinical-decision support. — Clifford A. Hudis, MD

Dr. Posner is Associate Chief of Pulmonary Medicine at Lenox Hill Hospital in New York.

MORE IN THIS ISSUE

A Conversation with Clifford A. Hudis, MD, ASCO’s President-Elect

fter six recurrences of colorectal cancer, the chances it will recur again are high. But if I concentrate on that, I couldn’t live my life. In retrospect, I should have paid attention sooner to the abdominal pain I was experiencing and not dismiss it as a simple case of gas. But at age 47 and with a busy medical practice to run, I couldn’t imagine that something bad was happening to my health. When I finally saw my internist 2 months later, he diagnosed appendicitis and I was rushed into surgery. When the pathology report came back it showed that I had a malignant mass near the cecum, and I was prescribed intraperitoneal chemotherapy. That was 10 years ago.

Study Details

Expert’s Corner

n June, Clifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service and Attending Physician at Memorial Sloan-Kettering Cancer Center, and Professor in the Department of Medicine at Weill Cornell Medical College, will begin his term as President of ASCO. Among Dr. Hudis’ priorities will be to oversee the continued

By David Posner, MD, as told to Jo Cavallo

CancerLinQ Prototype The CancerLinQ breast cancer prototype was unveiled at ASCO’s Quality Care Symposium this past November. What is the next step in the development of the prototype? We have loaded de-

Oncology Meetings Coverage Genitourinary Cancers Symposium �� 3, 7, 8 Gastrointestinal Cancers Symposium �� 10, 11, 18, 59, 60 FDA Update ��2, 20, 22, 77 Hematology �� 31, 33, 34 Palliative Radiotherapy in Lung Cancer �� 36 Direct from ASCO ��46-50 Breast Cancer �� 62, 63, 68, 69 Can Exercise Lengthen Cancer Survival? �� 114

continued on page 27

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A Harborside Press® Publication

The ASCO Post | MARCH 15, 2013

PAGE 2

FDA Update Breast Cancer

T-DM1 for HER2-positive Metastatic Breast Cancer Receives FDA Approval

Editorial Board James O. Armitage, MD Editor-in-Chief

Michael P. Link, MD Stanford University Medical Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Associate Editors

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology

William T. McGivney, PhD Philadelphia, Pennsylvania James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

E. David Crawford, MD University of Colorado

International Editors

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

George D. Demetri, MD Dana-Farber Cancer Institute

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Bishoy Morris Faltas, MD Weill Cornell Medical College John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

he FDA approved the antibodydrug conjugate ado-trastuzumab emtansine (Kadcyla), referred to as T-DM1 during clinical research, for patients with HER2-positive, metastatic breast cancer who were previously treated with trastuzumab (Herceptin) and taxane chemotherapy. Ado-trastuzumab emtansine was reviewed under the FDA’s priority review program. Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research said “[The new treatment] delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival. It is the fourth approved drug that targets the HER2 protein.”

Study Details The safety and effectiveness of adotrastuzumab emtansine were evaluated in a clinical study of 991 patients randomly assigned to receive ado-trastuzumab emtansine or lapatinib (Tykerb) plus capecitabine (Xeloda). Patients received treatment until either the cancer pro-

gressed or the side effects became intolerable. The study was designed to measure progression-free survival and overall survival. Results showed that patients treated with ado-trastuzumab emtansine had a median progression-free survival of 9.6 months compared to 6.4 months in patients treated with lapatinib plus capecitabine. The median overall survival was 30.9 months in the adotrastuzumab emtansine group and 25.1 months in the lapatinib plus capecitabine group. The most common side effects reported in patients treated with adotrastuzumab emtansine were nausea, fatigue, pain in the muscles or joints, thrombocytopenia, increased levels of liver enzymes, headache, and constipation. Ado-trastuzumab emtansine is being approved with a Boxed Warning alerting patients and health care professionals that the drug can cause liver toxicity, heart toxicity and death. The drug can also cause severe lifethreatening birth defects, and pregnancy status should be verified prior to starting treatment. n

Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®,LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $259; Individual International: $499; Institutional Domestic: $319; Institutional International $559. Contact subscriptions@harborsidepress.com.

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PAGE 3

Genitourinary Cancers Symposium Genitourinary Oncology

Reduced Risk of PSA Failure with Adjuvant Radiotherapy vs Wait-and-see Approach in Stage T3 Prostate Cancer By Alice Goodman

xtended follow-up of the German ARO 96-02 trial shows that adjuvant radiotherapy reduces the risk of biochemical failure in men whose prostate cancer extends through the prostate capsule (stage T3), compared with a wait-and-see approach, after radical prostatectomy. Adjuvant radiotherapy reduced the risk of biochemical failure (rising prostate-specific antigen [PSA] level) by 49% at 10 years in this study. The study was not powered to detect differences in overall survival, explained presenting author Thomas Wiegel, MD, University of Ulm, Germany, at the Genitourinary Cancers Symposium held recently in Orlando, Florida.1 “Our long-term follow-up shows that it is incorrect to say that adjuvant radiation for patients with positive surgical margins stage is over-

treatment. It is clear that adjuvant radiotherapy reduces biochemical evidence of disease after 10 years. It is quite important that we had a low rate of side effects, with only one case of grade 3 late toxicity,” he stated.

Study Design The study randomly assigned 385 men with stage T3 prostate cancer following radical prostatectomy in a 1:1 ratio to adjuvant radiotherapy vs a wait-and-see approach. Patients were randomized before they had an undetectable PSA level (< .05 ng/ mL). The median number of positive nodes was eight; median follow-up was 112 months. A total of 45 patients in the adjuvant radiotherapy arm and 33 in the wait-and-see arm failed to achieve an undetectable PSA level and were excluded from the analysis as planned.

EXPERT POINT OF VIEW

ow there are mature data from three trials comparing adjuvant radiotherapy vs a wait-and see approach in men following radical prostatectomy, said formal discussant Anthony D’Amico, MD, Dana-Farber Cancer Center and Harvard Medical School, Boston, at the Genitourinary Cancers Symposium. Despite the variations in patient population in these trials, all three showed a clear benefit for adjuvant radiotherapy in biochemical recurrence. However, these trials had different findings for other clinical endpoints. Dr. D’Amico believes that the differences in clinical outcomes among these trials may be acAnthony D’Amico, MD counted for by different methods of ascertaining failure and differences in the timing of initiating salvage therapy in the watchful waiting arm. “It is possible that early salvage therapy with PSA < 0.1 ng/mL may produce the same results as adjuvant radiotherapy. We await the results of two randomized trials—RADICALS and RAVES—to answer this question,” he stated. Until the results of these ongoing trials are available, Dr. D’Amico said that to reduce overtreatment, the decision to initiate adjuvant radiotherapy should be based on the number of risk factors for recurrence, including Gleason score, surgical margin status, and extension into the seminal vesicles or through the capsule. n Disclosure: Dr. D’Amico reported no potential conflicts of interest.

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

Adjuvant Radiotherapy in Prostate Cancer ■■ Three large randomized trials have shown that adjuvant radiotherapy after prostatectomy reduces biochemical failure in men with prostate cancer extending through the capsule.

■■ Results of these trials are inconsistent regarding a survival benefit. ■■ Treating stage T3 prostate cancer with adjuvant radiotherapy does not appear to be overtreatment but should be based on risk factors.

Another 34 patients in the adjuvant radiotherapy arm refused treatment. The intent-to-treat analysis was based on 148 patients in the adjuvant radiotherapy arm and 159 in the wait-and-see arm. All patients had stage T3 disease; 27% had T3c (extension of cancer to the seminal vesicles). The majority of patients had Gleason scores ranging from 7 to 9.

Major Findings At 10 years, freedom from biochemical failure was achieved in 56% of the adjuvant radiotherapy arm vs 35% of the wait-and-see arm, for an absolute difference of 21% favoring adjuvant treatment (P = .00002). No significant benefit was observed for adjuvant radiotherapy regarding metastasis-free survival or overall survival, although the trial was not powered to show this. For patients with positive surgical margins, adjuvant radiotherapy had a clear advantage: Biochemical control was achieved in 55% vs 27% of those in the wait-and-see arm, for an absolute difference of 28%. Baseline factors associated with greater efficacy of adjuvant radiotherapy included higher Gleason scores, higher PSA levels, and more aggressive tumors. In a multivariate analysis, adjuvant radiotherapy reduced the risk of biochemical failure by 54%. “The relative risk of biochemical failure was reduced for patients with positive surgical margins, higher PSA level, stage T3a/b, and higher Gleason scores,” he said.

Earlier Trials The rate of late side effects from radiation was quite low, especially compared to two similar previous trials conducted by the Southwest Oncology Group (SWOG)2 and the European Organisation for Research and Treatment of Cancer (EORTC).3 Dr. Wiegel said that in the SWOG trial, adjuvant radiotherapy not only reduced the rate of biochemical failure but also improved metastasis-free and overall survival at 12 years. The EORTC trial showed a 20% improvement in biochemical failure but no survival advantage. “Our trial is the only clear adjuvant trial, because it is the only trial where patients had an undetectable PSA before receiving radiotherapy,” Dr. Wiegel stated. n Disclosure: Dr. Wiegel reported no potential conflicts of interest.

References 1. Wiegel T, Bottke D, Bartkowiak D, et al: Phase III results of adjuvant radiotherapy versus wait-and-see in patients with pT3 prostate cancer following radical prostatectomy (ARO96-02/AUO AP 9/95). 2013 Genitourinary Cancers Symposium, Abstract 4. Presented February 14, 2013. 2. Thompson IM Jr, Tangen CM, Paradelo J, et al: Adjuvant radiotherapy for pathologically advanced prostate cancer. JAMA 296:2329-2335, 2006. 3. Bolla M, van Poppel H, Tombal B, et al: Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer. Lancet 380:2018-2027, 2012.

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

Important Safety Information

Additional Important Safety Information

Boxed WARNING: Embryo-Fetal Toxicity • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant — Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Left Ventricular Dysfunction • Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • Withhold PERJETA and Herceptin and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further Infusion‑Associated Reactions, Hypersensitivity Reactions/Anaphylaxis • PERJETA has been associated with infusion and hypersensitivity reactions • When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

F O R T H E F I R S T‑ L I N E T R E AT M E N T O F H E R 2 +* M E TA S TAT I C B R E A S T C A N C E R

STRENGTHEN HER DEFENSE

Indication: PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2‑positive metastatic breast cancer who have not received prior anti‑HER2 therapy or chemotherapy for metastatic disease.

Extend progression‑free survival (PFS) with an FDA‑approved HER2 dimerization inhibitor1,2 were observed across several • Consistent PFS results 1

•

Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR = 0.62‡ 95% CI [0.51‑0.75] P<0.0001

80 70

18.5 MONTHS

60 PFS (%)

•

patient subgroups At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1 The most common adverse reactions (ARs) (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

6.1-Month Improvement in Median IRF†-Assessed PFS1

12.4 MONTHS

40 30 20 10 0

* HER2+ = human epidermal growth factor receptor 2 positive. † IRF = independent review facility. ‡ Stratified by prior treatment status and geographic region.

402 406

345 311

267 209

139 93

32 17

10 7

0 0

MONTHS P+H+D Pl+H+D

83 42 Patients at risk

• In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis

was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. You may report side effects to the FDA at (800) FDA‑1088 or www.fda.gov/ medwatch. You may also report side effects to Genentech at (888) 835‑2555. For more information, scan the QR code or visit www.PERJETA.com.

PER0001010502

References: 1. PERJETA Prescribing Information. Genentech, Inc. June 2012. 2. Baselga J, Cortés J, Kim S‑B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109‑119.

Printed in USA.

(01/13)

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

ASCOPost.com | MARCH 15, 2013

PAGE 7

Genitourinary Cancers Symposium Genitourinary Oncology

Novel Antiandrogen Shows Encouraging Phase II Results in High-risk Nonmetastatic Castrate-resistant Prostate Cancer By Alice Goodman

reliminary results of a phase II study suggest that a novel antiandrogen called ARN-509 is safe, well tolerated, and has promising activity in high-risk nonmetastatic castrate-resistant prostate cancer. ARN-509 is a novel, second-generation, oral antiandrogen that binds directly to the ligand-binding domain of the androgen receptor, impairing nuclear trans-

enrolled in a phase I study. Across all dose levels, the drug achieved decline in prostate-specific antigen (PSA) level. Going forward in phase II trials, the recommended dose was 240 mg/d. Phase II studies are ongoing at 15 institutions in the United States in three cohorts of patients: high-risk nonmetastatic castrate-resistant prostate cancer, treatment-naive metastatic disease, and progressive disease after abiraterone (Zytiga) therapy. “ARN-509 is designed to be useful

ARN-509 is designed to be useful when first-generation antiandrogens such as bicalutamide fail. Our results to date support the further development of ARN-509 in prostate cancer. —Matthew R. Smith, MD, PhD

location and DNA binding. In contrast with bicalutamide, ARN-509 has no significant agonist properties in prostate cancer cells that overexpress the androgen receptor.

Clinical Trials Phase I studies of the novel compound have been completed. ARN-509 was safe and well tolerated in 30 men with castrate-resistant prostate cancer

when first-generation antiandrogens such as bicalutamide fail. Our results to date support the further development of ARN-509 in prostate cancer,” stated Matthew R. Smith, MD, PhD, Director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center, Boston, who presented preliminary results for the cohort with high-risk nonmetastatic castrate-resistant pros-

ARN-509 in Prostate Cancer ■■ Based on high PSA response rates, the novel antiandrogen ARN-509 has

proven safe and well tolerated with promising preliminary activity in men with high-risk nonmetastatic castrate-resistant prostate cancer.

■■ At 12 weeks, 91% of patients had a PSA response. The treatment effect

was durable, with a 91% PSA response rate at 24 weeks and an estimated 12-month progression-free survival of 88.7%.

Visit

EXPERT POINT OF VIEW

“T

he durability of PSA response is encouraging [with ARN-509], as is the toxicity data, but these are relatively asymptomatic patients,” said formal discussant William Oh, MD, Chief of the Division of Hematology and Medical Oncology, Professor of Medicine and Urology, and the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics at Icahn School of Medicine at Mount Sinai, New York, at the Gastrointestinal Cancers Symposium. “The data in mice showed that this agent had a greater effect in prostate cancer models than MDV3100, but it is too soon to say whether more potent androgen receptor inhibition seen in mice will translate to benefits for our patients. It is also too early to tell whether the effects of this drug will be clinically meaningful, but my instinct tells me it will be incrementally better than the recently approved antiandrogen agents.” n Disclosure: Dr. Oh is a consultant for Medivation, Astellas, and Janssen.

tate cancer at the Genitourinary Cancers Symposium.1 Promising results in patients with metastatic castrate-resistant prostate cancer, including treatment-naive disease and post-abiraterone progressive disease, were presented at the European Society for Medical Oncology (ESMO) 2012 Congress.2

Study Details The cohort reported by Dr. Smith included 47 patients with high-risk nonmetastatic castrate-resistant prostate cancer; of these, 41 were on ongoing treatment at the time of the Genitourinary Cancers Symposium. Of the 6 discontinuations, 2 were for progressive disease, 2 were for adverse events, and 2 for other reasons. At baseline, all men had PSA ≥ 8 ng/mL and PSA doubling time ≤ 10 months. Median age was 71 years. Approximately 32% had Gleason scores of 8 to 10, and median PSA was 10 ng/mL. All patients were previously treated with a luteinizing hormone-releasing hormone (LHRH) analog with or without a first-generation antiandrogen.

The primary endpoint was PSA response (defined as PSA decline ≥ 50%) at 12 weeks. At that time, 91% of patients had a PSA response. The same proportion of patients had a PSA response after 24 weeks, consistent with a durable treatment effect. The estimated 12-month progression-free survival was 88.7%. The drug was well tolerated. The most common adverse events were grade 1 or 2 fatigue and gastrointestinal disturbances. The incidence of grade 3 adverse events was 6.4%, and no seizures have been reported to date. n

Disclosure: Dr. Smith has served as a consultant for Aragon Pharmaceuticals.

References 1. Rathkopf DE, Antonarakis ES, Shore ND, et al: ARN-509 in men with metastatic castration-resistant prostate cancer. 2012 ESMO Congress. Abstract 964TiP. Presented September 29, 2012. 2. Smith MR, Antonarakis ES, Ryan CJ, et al: ARN-509 in men with high-risk non-metastatic castration-resistant prostate cancer. 2013 Genitourinary Cancers Symposium. Abstract 7. Presented February 14, 2013.

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The ASCO Post | MARCH 15, 2013

PAGE 8

Genitourinary Cancers Symposium Genitourinary Oncology

Did Corticosteroids Worsen Survival in Patients with Metastatic Prostate Cancer Enrolled in the AFFIRM Trial? By Alice Goodman

post hoc analysis of the AFFIRM trial found that on-study use of corticosteroids led to worse outcomes in metastatic castration-resistant prostate cancer regardless of whether patients were randomly assigned to enzalutamide (Xtandi) or placebo.1 On-study corticosteroid use was associated with reduced survival and higher rates of grade 3

Howard I. Scher, MD

or 4 adverse events. Regardless of onstudy corticosteroid use, enzalutamide remained consistently superior to placebo. Presenting author Howard I. Scher, MD, Chief, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, told listeners at the Genitourinary Cancers Symposium that AFFIRM was not designed to assess the efficacy of corticosteroids on survival. “Nevertheless, those patients taking corticosteroids had reduced survival times and higher grades of serious side effects than those who did not in this post hoc analysis. These findings require prospective validation,” Dr. Scher stated.

Study Background Enzalutamide is a novel oral androgen receptor inhibitor that blocks nuclear translocation of the androgen receptor as well as DNA binding. The randomized phase�� III AFFIRM trial found that baseline use of corticosteroids was associated with inferior overall survival. Without

corticosteroids, median overall survival was 7.5 months longer and risk of death was reduced by 53%.2 “Corticosteroids have a range of favorable effects in prostate cancer management. These include antitumor effects, palliation of symptoms, and reduction of adverse events associated with the administration of approved therapies. They are used in both the pre- and postchemotherapy settings, but now a body of evidence suggests that corticosteroids may stimulate prostate cancer growth by a range of mechanisms including the activation of promiscuous androgen receptors,” Dr. Scher explained. In the AFFIRM registration trial, enzalutamide prolonged survival in post–chemotherapy-treated metastatic castration-resistant prostate cancer by a median of 4.8 months, with a 37% reduction in risk of death. Dr. Scher and coauthors performed an unplanned post hoc analysis to determine if on-study use of corticosteroids compromised outcomes. In the study, patients were allowed to enter the trial on corticosteroids, but use of these agents varied widely, he continued. “Some patients did not take them at all, about 30% were taking them at the start of therapy, and others received them during the study,” he said. Overall, corticosteroids were used at the start of therapy and on study in 48% of enzalutamide recipients and 45% of the placebo group. Patients taking corticosteroids were generally sicker and had more advanced disease; they had poorer survival and more rapid disease progression.

Key Data Median survival for on-study corticosteroid users was 12.8 months for

Corticosteroid Use in Patients with Prostate Cancer ■■ A post hoc analysis of the AFFIRM trial showed that on-study corticosteroid use was associated with reduced survival and more grade 3/4 treatmentemergent adverse events in patients with metastatic castrate-resistant prostate cancer.

■■ Enzalutamide was consistently superior to placebo in patients taking and not taking on-study corticosteroids.

■■ The underlying explanation for these results may be that corticosteroids are used in sicker patients.

EXPERT POINT OF VIEW

ormal discussant William K. Oh, MD, Chief of the Division of Hematology and Medical Oncology, Professor of Medicine and Urology, and the Ezra M. Greenspan, MD, Professor in Clinical Cancer Therapeutics at Icahn School of Medicine at Mount Sinai, New York, was not convinced that corticosteroids were responsible for the poor outcomes in patients with on-study use of these drugs. In his opinion, use of corticosteroids appears to be a marker for much sicker patients, which may have accounted for the outcomes in the post hoc analyWilliam K. Oh, MD sis of AFFIRM. “Dr. Scher said that patients taking on-study corticosteroids were generally sicker, but I would argue that they were much sicker. I went online with the Memorial Sloan-Kettering nomogram and found a 4-month difference in survival based on patient characteristics of the two groups. The real question is why patients were on steroids. Are the steroids bad or are they just used in bad situations?” he commented. In most clinical trials, prednisone is used in both comparator arms, he continued. Three randomized trials in castrate-resistant prostate cancer have been conducted where prednisone was given only in one arm; two out of three studies actually showed that the prednisone arm was associated with improved survival when administered with docetaxel, he noted. “My conclusion is that corticosteroid use is associated with a bad phenotype. I did not see any data to suggest that prednisone itself was inducing poor response. We would need a prospective clinical trial to study this,” Dr. Oh said. n Disclosure: Dr. Oh is a consultant for Medivation, Astellas, and Janssen.

the enzalutamide arm vs 9.6 months for placebo (P < .001). For those not taking corticosteroids, the median survival was not yet reached in the enzalutamidetreated patients vs 18.8 months for placebo (P < .001). A similar pattern was seen for progression-free survival and time to prostate-specific antigen (PSA) progression. Corticosteroid-treated patients had inferior outcomes relative to those not taking corticosteroids, while the benefit of enzalutamide relative to placebo was seen in both corticosteroid- and noncorticosteroid-treated patients. Median progression-free survival was 5.6 vs 2.9 months, respectively, in on-study corticosteroid users, and 11.1 vs 3 months, respectively, in patients who did not use corticosteroids (P < .001 for both comparisons). Median time to PSA progression in on-study corticosteroid users was 5.6 months for enzalutamide vs 3.1 months for placebo (P < .001), and among nonusers, 8.6 vs 2.9 months, respectively (P < .001). Use of on-study corticosteroids was

associated with higher rates of treatmentemergent grade 3 and 4 adverse events, including anemia, fatigue, spinal cord compression, and back pain. Both the benefit of enzalutamide and the adverse effect of corticosteroids on outcomes remained in a multivariate analysis addressing imbalances in the groups. “Importantly, these findings are not definitive and require prospective validation,” Dr. Scher commented. n Disclosure: Dr. Scher has received research funding and other remuneration from Medivation.

References 1. Scher HI, Fizazi K, Saad F, et al: Impact of on-study corticosteroid use on efficacy and safety in the phase III trial of enzalutamide (ENZA), an androgen receptor inhibitor. 2013 Genitourinary Cancers Symposium. Abstract 6. Presented February 14, 2013. 2. Scher HI, Fizazi K, Saad F, et al: Association of baseline corticosteroid with outcomes in a multivariate analysis of the phase 3 AFFIRM trial of enzalutamide versus placebo. 2012 ESMO Congress. Abstract 899PD. Presented September 30, 2012.

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The ASCO Post | MARCH 15, 2013

PAGE 10

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Targeted Therapy Gaining Ground in the Second-line Treatment of Gastric Cancer By Caroline Helwick

n gastric cancer, the concept of targeted therapy assumed clinical significance when the addition of trastuzumab (Herceptin) to chemotherapy improved survival by almost 3 months in the ToGA trial.1 Another anti-HER2 agent, lapatinib (Tykerb), now looks promising, as does an agent targeting the vascular endothelial growth factor (VEGF) pathway, ramucirumab. Data presented at the 2013 Gastrointestinal Cancers Symposium validated the concept of using targeted agents in a disease that, until fairly recently, depended on cytotoxic chemotherapy to only marginally improve outcomes, said Neal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, the ASCO representative on the symposium’s news planning committee. “Five years ago all we had in stomach cancer were toxic drugs that we

piled on top of each other with only modest improvements, and a lot of toxicity. Now, we see drugs adding benefit without many side effects. This is further opening the door into targeting pathways, rather than using a blind shot,” Dr. Meropol told The ASCO Post.

Ramucirumab Improves Survival In a study that drew a large crowd at the poster presentation, an international team of investigators reported an improvement in overall survival with the anti-VEGF monoclonal antibody ramucirumab in metastatic gastric cancer progressing after firstline treatment.2 Patients who received ramucirumab as a single agent had a median overall survival of 5.2 months, compared to 3.8 months for placebo, translating into a 28% reduced risk of dying (P = .0473). Ramucirumab conferred a significant 52% reduction in the risk of progression. Median progression-free survival was 2.1 months with ramucirumab vs 1.3 months with placebo,

EXPERT POINT OF VIEW

eal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, commented that the quality of the data on ramucirumab is “very high,” and therefore, “we can believe these results.” The magnitude of the benefit, however, is “modest,” he pointed out. “This is not a home run, but ramucirumab is generally well tolerated, and for the patient with advanced cancer who is looking at toxic chemotherapy as their other treatment option, this may be preferable.” He also noted that this study evaluated the drug as a single agent, and suggested that greater benefit might be achieved in combination with chemotherapy, as was demonstrated with trastuzumab. The findings for the TyTAN study are encouraging for the HER2-enriched subset, he noted, and provide proof that “perturbing the HER2 pathway by means other than trastuzumab is of benefit.”

Need for Quality-of-life Data Johanna C. Bendell, MD, Director of the GI Cancer Research Program at the Sarah Cannon Research Institute, Nashville, commented that clinical trials are showing survival improvements with second-line chemotherapy, and now with targeted therapy. “But the benefits are not huge, and we need to ask, ‘If we can help patients live longer, can we also help them live better?’ We need quality-of-life data for this. Also, can we select patients who will most likely benefit from additional treatment so we can appropriately triage them?’” she said. “We still have far to go, but we are making steps forward.” n Disclosure: Drs. Meropol and Bendell reported no potential conflicts of interest.

Charles Fuchs, MD, MPH

and 12-week progression-free survival was 40% vs 16%, respectively. “The findings suggest that ramucirumab is a potential new second-line treatment in this patient population,” said Charles Fuchs, MD, MPH, Director of the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute, Boston. VEGF and VEGF receptor 2– mediated signaling and angiogenesis may contribute to gastric cancer pathogenesis. Ramucirumab is a fully human IgG1 monoclonal antibody targeting VEGF receptor 2. The placebo-controlled, doubleblind, randomized phase III international trial evaluated ramucirumab (8 mg/kg IV) vs best supportive care in 355 patients with metastatic gastric or gastroesophageal junction adenocarcinoma progressing on first-line platinum- and/or fluoropyrimidinecontaining combination therapy. The primary endpoint was overall survival. “The preliminary assessment found that overall survival and progression-free survival favored ramucirumab within each of the individual strata of the prespecified stratification factors. These included weight loss, geographic region, and location of the primary tumor,” Dr. Fuchs said. The overall response rate was low for both—3.3% and 2.6%, respectively—but the disease control rate was doubled with ramucirumab, 48.9% vs 23.1% (P < .0001). The drug was well tolerated, with grade 3/4 adverse events occurring in no more than 8% of patients on ramucirumab. Treatment-emergent deaths were similar between the arms, 10.6% with ramucirumab and 13.0% with placebo. Discussing the findings, Dr. Fuchs discussed how ramucirumab might be used, hypothetically. “One could

take this in several different directions. We could apply it as a single agent or combine it with chemotherapy in a relatively unselected population. We could also think in terms of biology, and identify subgroups in whom we would give it in combination with another biologic, perhaps another modulator of the VEGF pathway with which it would be synergistic—and give no cytotoxics at all. This would minimize toxicity and hopefully achieve the same efficacy,” he suggested.

Second-line Lapatinib plus Paclitaxel In another presentation of interest, Yung-Jue Bang, MD, Director of the Clinical Trials Center at Seoul National University Hospital in South Korea, presented the results of the TyTAN trial, which enrolled 261 HER2-amplified Asian patients

Yung-Jue Bang, MD

with advanced gastric cancer who progressed after first-line treatment.3 They were randomly assigned to receive paclitaxel (80 mg/m2 day 1, 8, 15 every 28 days) alone, or paclitaxel plus lapatinib at 1,500 mg/d. The combination led to a nonsignificant 2.1-month improvement in overall survival. Among the prespecified subgroup of patients with strong HER2 positivity, however, statistically significant benefits were shown for the combination in both overall survival and progression-free survival, Dr. Bang reported. Median overall survival was 11.0 months with lapatinib/paclitaxel vs 8.9 months with paclitaxel alone (HR = 0.84; P = .208). Progressionfree survival was 5.4 vs 4.4 months, respectively (HR = 0.85; P = .24). In patients with HER2 expression by immunohistochemistry (IHC) of continued on page 11

ASCOPost.com | MARCH 15, 2013

PAGE 11

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Second-line Docetaxel Improves Esophageal and Gastric Cancer Survival By Caroline Helwick

©ASCO/Todd Buchanan 2013

phase III study from the United Kingdom has shown that secondline treatment with docetaxel improves overall survival of patients with advanced esophagogastric cancer.1 The strategy has already been widely adopted, but COUGAR-02 is the first study to provide definitive evidence of a survival benefit with docetaxel given in the second-line setting, said Hugo Ford, MD, of Addenbrooke’s Hospital

lack of robust quality-of-life data,” he said. “This is the first definitive trial of second-line chemotherapy in a Western population, and it was adequately powered to include robust quality-of-life assessments. In this well-defined and homogeneous poorprognostic group, docetaxel provided

In this ... poor-prognostic group, docetaxel provided a significant overall survival benefit over active symptom control, with improvements in pain scores and no loss in global quality of life. —Hugo Ford, MD

in Cambridge, United Kingdom, at the 2013 Gastrointestinal Cancers Symposium in San Francisco. Patients with advanced disease who relapse after first-line chemotherapy have a median overall survival of only 3 months. Recent studies have suggested that second-line treatment may extend survival. “The current practice in the United States and much of Europe is to give second-line chemotherapy, even though the evidence isn’t as strong as we would like and there has been a

Targeted Therapy continued from page 10

IHC 3+, median overall survival was 14.0 months, vs 7.6 months with paclitaxel alone (HR = 0.59; P = .0176), and progression-free survival was 5.6 months vs 4.2 months, respectively (HR = 0.54; P = .0101). “One of the major reasons for the negative outcome may be the unexpectedly high proportion of IHC

a significant overall survival benefit over active symptom control, with improvements in pain scores and no loss in global quality of life.” According to Dr. Ford, the study confirms docetaxel as a standard second-line therapy after failure of platinum/fluoropyrimidine in selected patients with advanced esophagogastric cancer.

Study Details COUGAR-02 enrolled 168 patients with locally advanced or meta0/1+ patients in the study—35%,” Dr. Bang suggested. “Among the subgroup in the prospectively defined IHC 3+ subgroup, however, a significant benefit was observed in both overall and progression-free survival.” The incidence of diarrhea was 77% with the combination and 22% with paclitaxel, and was grade 3/4 in 18% and 2%, respectively. n Disclosure: Dr. Fuchs has served in a

Second-line Targeted Therapy in Gastric Cancer ■■ Ramucirumab, given after progression on first-line treatment, led to a

significant improvement in overall survival and progression-free survival.

■■ Lapatinib plus paclitaxel did not meet the primary endpoint in the TyTAN trial but in HER2 patients with IHC3+ expression, it led to a statistically significant doubling in overall survival.

static esophagogastric adenocarcinoma with disease progression within 6 months of first-line treatment. Patients were randomized to docetaxel (75 mg/m2 every 3 weeks for up to six cycles) or active symptom control, which included radiotherapy,

steroids, and/or supportive care. Partial responses to chemotherapy were observed in 7%, and disease was stabilized in 46%. Treatment with docetaxel significantly reduced mortality by 33%, imcontinued on page 17

EXPERT POINT OF VIEW

he study’s formal discussant, Johanna C. Bendell, MD, Director of Gastrointestinal Cancer Research and at the Sarah Cannon Research Institute, Nashville, said COUGAR02 had “good and appropriate stratification factors” and “importantly, included quality-of-life studies.” This is critical, she said, because the goal in treating the advanced gastric cancer population should be “not only to help them live longer but to live better.” Only about 20% of such patients receive secJohanna C. Bendell, MD ond-line treatment, she noted, largely because they are too ill. “The evidence that this is a difficult population to treat is the fact that, even within this clinical trial, only 23% receiving docetaxel and 36% receiving best supportive care completed their intended treatment,” she observed.

Confirms Previous Findings Consistent with findings from previous second-line studies, COUGAR-02 showed “that chemotherapy with docetaxel does benefit patients in the second line. Docetaxel and irinotecan [from prior trials] both work, but the overall benefit is still just about 1.5 months,” she emphasized. “Thus, maybe when making treatment decisions, we need to think about who will receive the most benefit,” Dr. Bendell suggested. “Here, it was patients with longer disease-free intervals and those with better performance status. Patients who responded did live longer and did feel better, and we should keep this in mind when thinking about treating this sick population.” n Disclosure: Dr. Bendell reported no potential conflicts of interest.

consultant or advisory role for Amgen, Bayer, Bristol-Myers Squibb, Genentech, Infinity Pharmaceuticals, Metamark Genetics, Momenta Pharmaceuticals, Pfizer, Roche, and Sanofi. Dr. Bang has served in a consultant or advisory role for GlaxoSmithKline, Roche, Pfizer, Novartis, Sanofi-Aventis, AstraZeneca, Merck, Bristol-Myers Squibb, Lilly, Bayer, Genentech, Amgen and has received honoraria from GlaxoSmithKline, Roche, Novartis, Pfizer, and Lilly.

References 1. Bang Y-J, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 376:687-697, 2012. 2. Fuchs CS, Tomasek J, Cho JY, et

al: REGARD: A phase III, randomized, double-blind trial of ramucirumab and best supportive care (BSC) versus placebo and BSC in the treatment of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing combination therapy. 2013 Gastrointestinal Cancers Symposium. Abstract LBA5. Presented January 24, 2013. 3. Bang Y-J, Ruihua X, Taroh S, et al: A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer in Asian population: TyTAN study. 2013 Gastrointestinal Cancers Symposium. Abstract 11. Presented January 24, 2013.

INDICATION: Iclusig™ (ponatinib) is a kinase inhibitor indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. This indication is based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

Introducing Iclusig™ (ponatinib) Unlock efficacy for resistant or intolerant CML and Ph+ ALL patients IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY See full prescribing information for complete boxed warning • Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. • Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusigtreated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity. Arterial Thrombosis: Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, has occurred in Iclusig-treated patients. Overall, 11% of patients experienced an arterial thrombosis event of any grade, and serious arterial thrombosis occurred in 8% of Iclusigtreated patients. 30 of 34 patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors. Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events. Hepatotoxicity: Hepatotoxicity that has resulted in liver failure and death occurred in 3 Iclusig-treated patients with BP-CML or Ph+ ALL. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver

function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated. Congestive Heart Failure: Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure (CHF) or left ventricular dysfunction (LVD), with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of CHF or LVD. Monitor patients for signs or symptoms consistent with CHF and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious CHF. Hypertension: Eight patients treated with Iclusig (2%) experienced treatmentemergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN. Hemorrhage: Serious bleeding events occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients.

C H R O N I C P H A S E C M L (C P - C M L )

More than half of CP-CML patients resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy achieved MCyR.

(144/267)

MCyR 95% CI: 48-60

44%

(118/267) CCyR 95% CI: 38-50

Most patients who achieved MCyR also achieved CCyR. Median duration of follow-up was 10 months.1

Response rates in CP-CML patients by number of prior TKIs.1

1 prior TKI

MCyR

(12/16) (95% CI: 48-93)

Iclusig is an oral medication taken once daily with or without food.

2 prior TKIs

MCyR

(63/98) (95% CI: 54-74)

≥3 prior TKIs

45%

MCyR

(69/153) (95% CI: 37-53)

Learn more about Iclusig efficacy in the T315I mutation and in all phases of resistant or intolerant CML and Ph+ ALL at Iclusig.com.

Iclusig was evaluated in a single-arm, open-label, international, multicenter trial. All patients were administered 45 mg of Iclusig once daily. Patients were assigned to one of six cohorts based on disease phase (chronic phase CML [CP-CML]; accelerated phase CML [AP-CML]; or blast phase CML [BP-CML]/Ph+ ALL), resistance or intolerance (R/I) to prior TKI therapy, and the presence of the T315I mutation. The primary efficacy endpoint in CP-CML was major cytogenetic response (MCyR).

The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage. Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated. Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended. Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy. Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig. The most common non-hematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia. Please see the brief summary of the Prescribing Information on the following pages, including the Boxed Warning. Note: Unless otherwise indicated, data presented are from Iclusig [package insert]. Cambridge, MA: ARIAD Pharmaceuticals, Inc.; 2012. Reference: 1. Data on file.

BRIEF SUMMARY Iclusig (ponatinib) Rx only Please consult full Prescribing Information, including Boxed Warning, available at Iclusig.com.

WARNING: ARTERIAL THROMBOSIS and HEPATOTOXICITY Arterial Thrombosis: • Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients. In clinical trials, serious arterial thrombosis occurred in 8% of Iclusig-treated patients. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].

required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 29% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations. 5.5

Clinical pancreatitis occurred in 6% (28/449) of patients (5% grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). Twenty-two of the 28 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Hepatotoxicity: • Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function prior to and during treatment. Interrupt and then reduce or discontinue Iclusig for hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.2)]. 1

INDICATIONS AND USAGE

5.6

This indication is based upon response rate [see Clinical Studies (14)]. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig. CONTRAINDICATIONS

5.7

WARNINGS AND PRECAUTIONS

5.1

Thrombosis and Thromboembolism Arterial Thrombosis

In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%).

Cardiovascular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke have occurred in Iclusig-treated patients.

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Serious arterial thrombosis occurred in 8% (34/449) of Iclusig-treated patients. Twenty-one patients required a revascularization procedure (16 patients with coronary revascularization, 4 patients with peripheral arterial revascularization, and 1 patient with cerebrovascular revascularization). Overall, fifty-one patients (11%) experienced an arterial thrombosis event of any grade.

5.8

Supraventricular tachyarrhythmias occurred in 25 (5%) Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. The other supraventricular tachyarrhythmias were atrial flutter (4 patients), supraventricular tachycardia (4 patients), and atrial tachycardia (1 patient). For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness).

Serious cerebrovascular events were reported in 2% (8/449) of Iclusig-treated patients. Two patients experienced hemorrhagic conversion of the initial ischemic event. Four patients developed stenosis of large arterial vessels of the brain (e.g., carotid, vertebral, middle cerebral artery). Serious peripheral arterial events were reported in 2% (7/449) of Iclusig-treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations. Thirty of 34 Iclusig-treated patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

5.9

5.10 Tumor Lysis Syndrome Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. Both cases occurred in patients with advanced CML. Hyperuricemia occurred in 7% (30/449) of patients, the majority had chronic phase CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig. 5.11 Compromised Wound Healing and Gastrointestinal Perforation No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Hepatotoxicity Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts. The incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing. 5.12 Embryo-Fetal Toxicity Iclusig can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. Ponatinib caused embryo-fetal toxicity in rats at exposures lower than human exposures at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig [see Use in Specific Populations (8.1)].

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)]. 5.3

Congestive Heart Failure Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

5.4

Hypertension Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients

M yelosuppression Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML) and Ph+ ALL than in patients with chronic phase CML (CP-CML). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

Venous Thromboembolism Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

C ardiac Arrhythmias Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 3 (1%) Iclusig-treated patients. The cardiac rhythms (1 case each) identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain).

Myocardial infarction or worsening coronary artery disease was the most common arterial thrombosis event and occurred in 21 patients (5%) of Iclusig-treated patients. Eleven of these patients developed congestive heart failure concurrent or subsequent to the myocardial ischemic event.

5.2

Fluid Retention Fluid retention events judged as serious occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. Serious fluid retention events in more than 1 patient included: pericardial effusion (6/449, 1%), pleural effusion (5/449, 1%), and ascites (2/449, <1%).

None 5

Hemorrhage Serious bleeding events, occurred in 5% (22/449) of patients treated with Iclusig, including fatalities. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Cerebral hemorrhage and gastrointestinal hemorrhage were the most commonly reported serious bleeding events. Most hemorrhagic events occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.9)]. Interrupt Iclusig for serious or severe hemorrhage [see Dosage and Administration (2.3)].

Iclusig™ (ponatinib) is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.

P ancreatitis

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reactions are discussed in greater detail in other sections of the prescribing information: • Thrombosis and Thromboembolism [see Warnings and Precautions (5.1)] • Hepatotoxicity [see Warnings and Precautions (5.2) and Dosage and Administration (2.3)] • Congestive Heart Failure [see Warnings and Precautions (5.3)]

• Hypertension [see Warnings and Precautions (5.4)] • Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)] • Hemorrhage [see Warnings and Precautions (5.6)] • Fluid Retention [see Warnings and Precautions (5.7)] • Cardiac Arrhythmias [see Warnings and Precautions (5.8)] • Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.9)] The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. At the time of analysis, the median duration of treatment with Iclusig was 337 days in patients with CP-CML, 362 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83%, of the expected 45 mg dose. Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 4. Overall, the most common non-hematologic adverse reactions (≥ 20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. The rates of treatment-emergent adverse events resulting in discontinuation were 13% in CPCML, 11% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse events that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%). Dose modifications (dose delays or dose reduction) due to adverse reactions occurred in 74% of the patients. The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), lipase increased (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and ALT, AST, or GGT increased (6%). Table 4: Adverse Reactions Occurring in >10% of Patients, Any Group CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) System Organ Class Any CTCAE Any CTCAE Any CTCAE Any CTCAE Grade Grade Grade Grade Grade Grade Grade Grade (%) 3/4 (%) 3/4 (%) 3/4 (%) 3/4 (%) (%) (%) (%) Cardiac or Vascular disorders Hypertension (a) 68 39 71 36 65 26 53 31 Arterial ischemia (b) 13 7 12 6 8 5 3 0 Cardiac Failure (c) 6 4 6 2 15 11 6 6 Gastrointestinal disorders Abdominal pain (d) 49 10 40 8 34 6 44 6 Constipation 37 2 24 2 26 0 47 3 Nausea 23 1 27 0 32 2 22 0 Diarrhea 16 1 26 0 18 3 13 3 Vomiting 13 2 24 0 23 2 22 0 Oral mucositis (e) 10 1 15 1 23 0 9 3 GI hemorrhage (f) 2 <1 8 1 11 5 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 <1 4 4 11 11 25 25 Infections and infestations Sepsis 1 1 5 5 8 8 22 22 Pneumonia 3 2 11 9 13 11 9 3 Urinary tract infection 7 1 12 1 0 0 9 0 Upper respiratory tract infection 11 1 8 0 11 2 0 0 Nasopharyngitis 9 0 12 0 3 0 3 0 Cellulitis 2 1 4 2 11 3 0 0 Nervous system disorders Headache 39 3 28 0 31 3 25 0 Peripheral neuropathy (g) 13 2 8 0 8 0 6 0 Dizziness 11 0 5 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 3 1 11 2 13 0 19 3 Cough 12 0 17 0 18 0 6 0 Dyspnea 11 2 15 2 21 7 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 54 5 48 8 39 5 34 6 Dry skin 39 2 27 1 24 2 25 0 Musculoskeletal and connective tissue disorders Arthralgia 26 2 31 1 19 0 13 0 Myalgia 22 1 20 0 16 0 6 0 Pain in extremity 17 2 17 0 13 0 9 0 Back pain 15 1 11 2 16 2 13 0 Muscle spasms 12 0 5 0 5 0 13 0 Bone pain 12 <1 12 1 11 3 9 3 General disorders and administration site conditions Fatigue or asthenia 39 3 36 6 35 5 31 3 Pyrexia 23 1 31 5 32 3 25 0 Edema, peripheral 13 <1 19 0 13 0 22 0 Pain 8 <1 7 0 16 3 6 3 Chills 7 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 8 <1 12 1 8 0 31 0 Investigations Weight decreased 6 <1 7 0 5 0 13 0 Psychiatric disorders 0 12 0 8 0 9 0 Insomnia 7

Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent, all causality events (a) derived from blood pressure (BP) measurement recorded monthly while on trial (b) includes cardiac, central nervous system, and peripheral arterial ischemia (c) includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure (d) includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort (e) includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration (f) includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage (g) includes burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, polyneuropathy

Table 5: Serious Adverse Reactions (SAR) Cardiovascular disorders Arterial ischemic event Myocardial infarction or worsening coronary artery disease Stroke or TIA Peripheral arterial disease Hemorrhage CNS hemorrhage Gastrointestinal hemorrhage Cardiac failure Effusions* Atrial fibrillation Venous thromboembolism Hypertension Gastrointestinal disorders Pancreatitis Abdominal pain Blood and lymphatic system disorders Febrile neutropenia Thrombocytopenia Anemia Infections Pneumonia Sepsis General Pyrexia

N (%) 34 (8%) 21 (5%) 8 (2%) 7 (2%) 22 (4%) 10 (2%) 10 (2%) 20 (4%) 13 (3%) 11 (2%) 10 (2%) 8 (2%) 23 (5%) 17 (4%) 13 (3%) 13 (3%) 12 (2%) 24 (4%) 11 (2%) 14 (3%)

*includes pericardial effusion, pleural effusion, and ascites

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 6). Table 6: Incidence of Clinically Relevant Grade 3/4* Hematologic Abnormalities Laboratory Test CP-CML AP-CML BP-CML Ph+ ALL (N=270) (N=85) (N=62) (N=32) (%) (%) (%) (%) Hematology Thrombocytopenia 36 47 57 47 (platelet count decreased) Neutropenia (ANC decreased) 24 51 55 63 Leukopenia (WBC decreased) 14 35 53 63 Anemia (Hgb decreased) 9 26 55 34 Lymphopenia 10 26 37 22 ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count *Reported using NCI-CTC-AE v 4.0

Table 7: Incidence of Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any Grade* Grade 3/4 (%) (%) Liver function tests ALT increased 53 8 AST increased 41 4 Alkaline phosphatase increased 37 2 Albumin decreased 28 1 Bilirubin increased 19 1 Pancreatic enzymes Lipase increased 41 15 Amylase increased 3 <1 Chemistry Glucose increased 58 6 Phosphorus decreased 57 8 Calcium decreased 52 1 Sodium decreased 29 5 Glucose decreased 24 0 Potassium decreased 16 2 Potassium increased 15 2 Sodium increased 10 <1 Bicarbonate decreased 11 <1 Creatinine increased 7 <1 Calcium increased 5 0 Triglycerides increased 3 <1 ALT=alanine aminotransferase, AST=aspartate aminotransferase. *Graded using NCI-CTC-AE v 4.0

DRUG INTERACTIONS Based on in vitro studies ponatinib is a substrate of CYP3A4/5 and to a lesser extent CYP2C8 and CYP2D6. Ponatinib also inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

7.1

Drugs That Are Strong Inhibitors of CYP3A Enzymes In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced to 30 mg once daily [see Dosage and Administration (2.1)]. Patients taking concomitant strong inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2

Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of Iclusig with strong CYP3A inducers was not evaluated in vitro or in a clinical trial; however, a reduction in ponatinib exposure is likely [see Clinical Pharmacology (12.3)]. Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s Wort) with Iclusig should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.3

Drugs That Elevate Gastric pH Coadministration of Iclusig with drugs that elevate the gastric pH was not evaluated in a clinical trial. Based on the chemical properties of ponatinib, elevated gastric pH may reduce bioavailability and exposure [see Clinical Pharmacology (12.3)]. Coadministration of Iclusig with drugs that elevate the gastric pH (e.g., proton pump inhibitors, H2 blockers, or antacids) should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure. Monitor patients for signs of reduced efficacy.

7.4

Drugs That Are Substrates of the P-gp or ABCG2 Transporter Systems In vitro studies demonstrate that Iclusig inhibits the P-gp and ABCG2 [also known as BCRP] transporter systems. The effect of coadministration of Iclusig with sensitive substrates of the P-gp (e.g., aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, saxagliptin, sirolimus, sitagliptin, tolvaptan, topotecan) and ABCG2 [also known as BCRP] (e.g., methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan) transporter systems on exposure of these substrates has not been evaluated in clinical studies.

USE IN SPECIFIC POPULATIONS

8.1

regnancy P Pregnancy Category D Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Iclusig in pregnant women. Advise women to avoid becoming pregnant while taking Iclusig. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis. At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.3

Nursing Mothers It is unknown whether ponatinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ponatinib, a decision should be made whether to discontinue nursing or to discontinue Iclusig, taking into account the importance of the drug to the mother.

8.4

Pediatric Use The safety and efficacy of Iclusig in patients less than 18 years of age have not been established.

8.5

Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (38%) as compared with patients < 65 years of age (64%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a higher major hematologic response rate (47%) as compared with patients < 65 years of age (40%). Patients of age ≥ 65 years may be more likely to experience adverse reactions including decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6

Hepatic Impairment Iclusig has not been studied in patients with hepatic impairment. As hepatic elimination is a major route of excretion for Iclusig, hepatic impairment may result in increased ponatinib exposure. Avoid Iclusig in patients with moderate to severe (Child-Pugh B or C) hepatic impairment unless the benefit outweighs the possible risk of ponatinib overexposure [see Clinical Pharmacology (12.3)]. Patients with moderate to severe hepatic impairment may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

8.7

Renal Impairment Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined [see Clinical Pharmacology (12.3)].

OVERDOSAGE Overdoses with Iclusig were reported in clinical trials. One patient was accidentally administered the entire contents of a bottle of study medication via nasogastric tube. The investigator estimated that the patient received 540 mg of Iclusig. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient accidentally self-administered 165 mg on cycle 1 day 2. The patient experienced fatigue and non-cardiac chest pain on day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion. In the event of an overdose of Iclusig, stop Iclusig, observe the patient and provide appropriate supportive treatment. Manufactured for: ARIAD Pharmaceuticals, Inc. 26 Landsdowne Street Cambridge, MA 02139-4234 For information contact: 1-855-55-ARIAD (855-552-7423) medinfo@ariad.com PB/0213/0103/US

ASCOPost.com | MARCH 15, 2013

PAGE 17

Gastrointestinal Cancers Symposium Second-line Docetaxel continued from page 11

proving median overall survival from 3.6 months in the control arm to 5.2 months in the docetaxel arm (P = .01), Dr. Ford reported. “Adjusting for prognostic factors, the treatment effect remained significant,” he said. This was most marked in those patients with longer diseasefree interval, but a consistent trend for improved survival with docetaxel was seen in patients with progression on or within 3 months of treatment. Among the subgroups, benefit was also notable for “very fit” patients with ECOG performance status of 0.

Docetaxel was associated with grade 4 toxicity in 21% of patients. Patients received a median of three cycles, and only 23% completed the full 18 weeks of treatment; most discontinuations were due to progressive disease (40%) and toxicity or symptoms (31%). For 28% of patients allocated to docetaxel, only zero or one cycle was possible, “which confirms the aggressive nature of this disease in some,” he said.

Quality of Life Preliminary assessments showed that “global quality-of-life scores and the functional quality-of-life

Second-line Docetaxel in Esophagogastric Cancer ■■ After experiencing disease progression on first-line chemotherapy,

patients with esophagogastric cancer lived significantly longer (by 1.6 months) and had less pain if they received second-line treatment with docetaxel, vs active symptom control.

■■ The most benefit was seen in patients with a longer disease-free interval and excellent performance status.

Neal J. Meropol, MD

scores were not affected by chemotherapy. In other words, the chemotherapy did not have an adverse effect on how people functioned,” Dr. Ford said. “The symptom scores were substantially better in the docetaxel arm, the most prominent of those being pain, which was markedly improved in the patients who received chemotherapy (P = .0008),” he added Benefits were seen across all groups, with no cohort of patients seeming to fare worse with chemotherapy, he added. Neal J. Meropol, MD, Professor

and Chief of Hematology/Oncology at University Hospitals Case Medical Center and Case Western Reserve University, Cleveland, who moderated a press briefing, commented that the COUGAR-02 study is “a model for providing an evidence base to help guide our treatment decisions at points in time when the goals are palliative and not curative, and a model for the type of study we would like to see more of. Treatment toward the end of life is an area where we have fallen a little short (regarding evidence) and we need to pay additional attention.” n

Disclosure: Dr. Ford has received research funding from Sanofi. Dr. Meropol reported no potential conflicts of interest.

Reference 1. Ford H, Marshall A, Wadsley J, et al: COUGAR-02: A randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophagogastric adenocarcinoma. 2013 Gastrointestinal Cancers Symposium. Abstract LBA4. Presented January 24, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Clifford A. Hudis, MD, on ASCO’s CancerLinQ Prototype see page 1

Howard Scher, MD, on the AFFIRM Trial in Metastatic Prostate Cancer see page 8

Richard M. Goldberg, MD, on A Decade of Progress in Colorectal Cancer see page 18

Eileen M. O’Reilly, MD, on New Strategies in Pancreatic Cancer see page 56

William L. Carroll, MD, on Superstorm Sandy and Emergency Preparedness see page 78

Saul N. Weingart, MD PhD, on Preventing Medical Errors in Oral Chemotherapy Prescribing see page 84

In Memoriam: Jane Cooke Wright, MD see page 91

Mark G. Kris, MD, on Supercomputers in Oncology Care see page 100

Sandra M. Swain, MD, FACP, on the Impact of Sequestration on Oncology see page 126

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | MARCH 15, 2013

PAGE 18

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Colorectal Cancer: A Decade of Progress By Caroline Helwick

he 2013 Gastrointestinal Cancers Symposium marked the 10th anniversary of the meeting. Richard M. Goldberg, MD, the Klotz Family Chair in Cancer Research, Professor of Medicine, and James Cancer Hospital Physician-in-Chief at The Ohio State University, looked back over the decade to highlight the important advances made—many reported just last year—in preventing, diagnosing, and treating cancers of the colon and rectum. “We have made great progress in the past decade, much of it reported at this meeting,” Dr. Goldberg said. “We have seen mortality reduced by 10%, and the curves are headed downward still. We have gone from a 6-month median overall survival with best supportive care to close to 30 months for incurable colorectal cancer (Fig. 1), which is a consequence of having more tools in our toolkit for the various permutations of this disease. That’s the real measure of what our efforts are doing,” he commented. “We are seeing the potential for universal Lynch syndrome screening. We are unraveling the mysteries of the genome, and this will impact our clinical practices. We have strategies for preventing colon cancer and its recurrence that patients can engage in. We have new screening tools, new surgical tools, new radiation tools, and additional drugs in our armamentarium,” he said. “The cup is more than half full.”

Lynch Syndrome “When the Symposium began in 2003, Henry Lynch had been pounding the podium for years, trying to convince the world that familial colon cancer existed. Today, we are aware of this,” Dr. Goldberg said. Some 2% to 3% of patients with colorectal cancer have Lynch syndrome, and not only can they be identified, but so can affected family members (averaging three per proband). Interventions can “prevent them from suffering the ravages of their inherited predisposition,” he said. A strong case is being made for universal screening of colorectal cancer, based on data that restricting screening to cases fitting the Amsterdam criteria

misses one-quarter of affected persons. Universal screening should result in the diagnosis of more than 15,000 individuals nationally. “This is evidence that molecular genetics is making a difference in the clinic,” he said.

Molecular Characterization of Tumors The Cancer Genome Atlas Network recently published a comprehensive molecular characterization of colon and rectal cancer.1 The key findings were that 16% of tumors are hypermutated, but only 75% are microsatellite instability–high, indicating “we need to understand more about the hypermutated subset,” he said. Also revealed were similar patterns of genomic alterations for colon and rectal cancers. In particular, some two dozen genes are significantly mutated, “many of which would have been predicted but some of which were unexpected,” he said. These can be exploited for therapeutic gain; druggable opportunities already exist for some (ERBB2 and IGF2). The identification and validation of gene-expression subtypes is now underway by many research groups. “In some ways, this is the Rosetta Stone we hope will allow us to translate clinical and genetic information into real advances for our patients,” Dr. Goldberg said.

Prevention Is Possible The potential for preventing primary or recurrent colorectal cancer is becoming more real. The observation that risk factors for developing cancer 35

overlap with those associated with outcomes means “the biology that is driving the occurrence of colorectal cancer is apparently driving the progression or lack of it,” he suggested. Observational studies in patients with stage I–III disease have yielded

—Richard M. Goldberg, MD

information that is clinically useful. Factors known to reduce the risk of recurrence include physical activity (> 10 MET-hours/wk), avoidance of a Western diet, avoidance of obesity (body mass index > 35 kg/m2), intake of aspirin or COX2 inhibitors, and high vitamin D levels. An intriguing new observation is that high glycemic load (ie, sugar intake) may raise the risk of recurrence or death by more than 200%.2 Recurrence has not been associated, however, with weight change (gain or loss), smoking status or history, and multivitamin intake. Also intriguing are recent findings that the protective effect of aspirin may vary according to PIK3CA mutation status. (Inhibition of COX2 by aspirin appears to down-regulate PI3 kinase signaling activity.) Among patients with mutated PIK3CA tumors,

5-FU Irinotecan

Capecitabine Oxaliplatin

Cetuximab

Panitumumab

Ziv-aflibercept Regorafenib

Median overall survival

Bevacizumab beyond progression

0 1980

1985

1990

1995

2000

2005

2010

Fig. 1: Advances in the treatment of stage IV colorectal cancer. Courtesy of Axel Grothey, MD.

molecular biomarker for adjuvant aspirin therapy, Dr. Goldberg said, adding that he now makes specific recommendations to patients about “diet and exercise, and the possibility of taking aspirin.”

Colorectal Cancer Screening The benefit of colonoscopy and polypectomy in reducing colorectal cancer deaths was established in 2012 in the National Polyp Study of 2,602 patients with adenomas removed between 1980 and 1990.4 By comparing deaths observed with those expected, a 53% reduction in mortality was achieved with polypectomy. In addition, CT colonography emerged as a new screening modality. In experienced hands, CT colonography has a sensitivity of about 96%,5 though clinician experience is critical for a good test. Not yet FDA-approved, fecal DNA is under evaluation as a widely accessible screening test requiring no cathartic preparation, dietary restriction, or visit to the physician’s office. Fecal DNA has shown 85% specificity for colorectal cancer and a 65% specificity for adenomas > 1 cm.6

Surgical and Radiation Advances

Bevacizumab

regular use of aspirin after diagnosis was associated with an 82% reduction in cancer-related mortality and a 46% reduction in all-cause mortality, but had no effect in those with wild-type PIK3CA.3 This suggests the PIK3CA mutation may serve as a predictive

We have made great progress in the past decade. We have gone from a 6-month median overall survival with best supportive care to close to 30 months for incurable colorectal cancer.

Best supportive care

30 Overall survival (months)

2015

The laparoscopic approach to colectomy proved comparable and in some ways superior to open surgery in a 2004 study of 872 patients.7 Recurrence rates, overall survival, and complications were similar between the arms, but the laparoscopic arm had faster recovery, shorter hospital stay,

ASCOPost.com | MARCH 15, 2013

PAGE 19

Gastrointestinal Cancers Symposium and less use of narcotics. The study showed that laparoscopically assisted colectomy “is just as good a cancer operation as open colectomy,” he said. The next surgical advance is robotics, although it is entering mainstream use without a proven track record. “The studies we are seeing are often retrospective comparisons. It is a technique many hospitals employ as a marketing tool, and we don’t know its relative efficacy, whether it’s a better operation,” Dr. Goldberg maintained. Advances have also been impressive with regard to the surgical resection of liver metastases. A recent meta-analysis showed that 5-year survival after resection was 40% and median overall survival was 3.6 years.8 Chemotherapy

then bevacizumab (Avastin), improved outcomes when added to irinotecan, fluorouracil, and leucovorin (IFL). Findings from these landmark studies, both published in 2004,10,11 changed the standard of practice across the world, he said. The controversy over the benefit of oxaliplatin in patients with stage II disease still simmers, he said, but large randomized trials—MOSAIC12 and the NSABP C-07 trial13—changed the standard of care for stage III patients. Confirmatory studies have shown a clear separation of disease-free survival curves in stage III patients and a trend toward overall survival benefit with oxaliplatin, but no differences among stage II patients. Therefore, oxaliplatin

Colorectal Cancer: 10 Years of Advances ■■ Decline in mortality by > 10% ■■ Potential for universal Lynch syndrome screening ■■ Unraveling the mysteries of the cancer genome ■■ Prevention of primary and recurrent disease ■■ New screening tools: CT colonography, fecal DNA ■■ Laparoscopic, robotic, and hepatic surgery ■■ Preoperative rectal chemoradiotherapy and Cyberknife ■■ New drugs: oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-aflibercept, regorafenib

can make some unresectable lesions resectable, though there remains a risk for chemotherapy-induced hepatic injury. Stereotactic radiotherapy for liver metastases is also promising, especially for problematically located lesions. “We are at an early stage in evaluating this modality, but many retrospective series are showing some value,” he said, citing local control rates exceeding 90% at 1 year. For rectal cancer, the standard of care shifted from postoperative to preoperative chemoradiotherapy. A recent 40-month update of a landmark study indicated a halving of local recurrence rates—from 12% to 6%—with less anastomotic stenosis or need for abdominal perineal resection.9

Landmark Studies A new era of chemotherapy for colorectal cancer began a decade ago, when the addition of oxaliplatin, and

should not be the standard of care for patients with routine-risk stage�� II disease, Dr. Goldberg said.

Additional Novel Agents A few years later, cetuximab (Erbitux) and panitumumab (Vectibix) proved capable of improving outcomes as well, at least in a subset of patients.14–16 These patients were soon identified when “the oncology world cried out for a biomarker to determine who was in that subset,” he said. “In many ways, the identification of KRAS as this marker was a seminal finding because it unlocked the door for using biomarkers to predict treatment benefits.” The pharmacologic advances that began in the late 1990s have continued with the rapid approval of two drugs in 2012, regorafenib (Stivarga) and ziv-aflibercept (Zaltrap). “These agents are also translating into better outcomes,” Dr. Goldberg said.

Ziv-aflibercept showed a benefit in the second-line setting, coupled with FOLFIRI (leucovorin, fluorouracil, irinotecan), improving overall survival by 1.5 months (HR = 0.817; �� .0032) and progression-free surP = vival by more than 2 months (HR = 0.758; P < .0001).17 Regorafenib, tested as a late-line treatment vs best supportive care, was similarly effective in the CORRECT trial, which showed a 1.4-month overall survival benefit (HR = 0.77; P = .0052).18 “The progression-free survival curves for regorafenib, cetuximab, and panitumumab mirror each other,” he said. “We have a genetic predictor for the last two, but we have not identified one for regorafenib. Work must continue on this, to determine how to select which patients to treat with a pricey drug that has some potential side effects.” n Disclosure: Dr. Goldberg has received research support from and has been an unpaid consultant for Bayer and Sanofi. He has also served on data monitoring boards for Pfizer and Lilly.

References 1. Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330-337, 2012. 2. Meyerhardt JA, Sato K, Niedzwiecki D, et al: Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst 104:17021711, 2012. 3. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012. 4. Zauber A, Winower SJ, O’Brien MJ, et al: Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 366:687-696, 2012. 5. Pickhardt PJ, Hassan C, Halligan S, et al: Colorectal cancer: CT colonography and colonoscopy for detection—systematic review and meta-analysis. Radiology 259:393-405, 2011. 6. Ahlquist DA, Zou H, Domanico M, et al: Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142:248256, 2012. 7. Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:20502059, 2004.

8. Kanas GP, Taylor A, Primrose JN, et al: Survival after liver resection in metastatic colorectal cancer: Review and metaanalysis of prognostic factors. Clin Epidemiol 4:283-301, 2012. 9. Sauer R, Liersch T, Merkel S, et al: Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ AOR/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30:1926-1933, 2012. 10. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004. 11. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004. 12. André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004. 13. Yothers G, O’Connell MJ, Alegra CJ, et al: Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07, including survival and subset analyses. J Clin Oncol 29:1768-1774, 2011. 14. Jonker DJ, O’Callaghan CJ, Karapetis C, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:20402048, 2007. 15. Van Cutsem E, Peeters M, Salvatore Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007. 16. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:16261634, 2008. 17. Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:34993506, 2012. 18. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international multicenter, randomized, placebo-controlled, phase 3 trial. Lancet 381:303-212, 2013.

The ASCO Post | MARCH 15, 2013

PAGE 20

FDA Update Hematology

Ibrutinib Receives Two Oncology Breakthrough Therapy Designations from FDA

anssen Research & Development, LLC, and Pharmacyclics, LLC, announced that the FDA has granted Breakthrough Therapy Designations for the investigational oral agent ibrutinib as a monotherapy for two B-cell malignancies: in patients with relapsed or refractory mantle cell lymphoma who have received prior therapy, and in patients with Waldenstrom’s macroglobulinemia. Enacted as part of the 2012 FDA Safety and Innovation Act, Breakthrough Therapy Designation is intended to expedite the development and re-

least one prior rituximab-containing chemotherapy regimen and who progressed after bortezomib (Velcade) therapy, SPARK (MCL2001).

A phase II single-arm study of ibrutinib as monotherapy in patients with relapsed or refractory mantle cell lymphoma (PCYC-1104).

Ongoing Collaboration

Janssen Biotech, Inc. and Pharmacyclics entered a collaboration and license Trim: agreement in December 2011 to co-de-

view time for a potential new medicine “to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”1

Clinical Trials The FDA Breakthrough Therapy Designation for ibrutinib in patients with mantle cell lymphoma was based on data from clinical and preclinical studies. Ibrutinib has the potential to improve the outcome in this serious and life-threatening disease which has a poor prognosis. Janssen and Pharmacyclics have designed a comprehensive development program of ibrutinib in mantle cell lymphoma which includes the following studies: A phase III randomized, multicenter registration trial of ibrutinib as a monotherapy vs temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least one prior rituximab (Rituxan)-containing chemotherapy regimen, RAY (MCL3001). A phase III randomized, doubleblind, placebo-controlled study of ibrutinib plus bendamustine (Treanda) and rituximab vs placebo plus bendamustine and rituximab in subjects with newly diagnosed mantle cell lymphoma, SHINE (MCL3002). A phase II single-arm study of ibrutinib as a monotherapy in patients with mantle cell lymphoma who received at

Simulated image based on locally advanced BCC patient at Week 24. Indication

Erivedge (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. ®

Boxed Warning and Additional Important Safety Information • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen

• Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation

• Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers

• Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

ASCOPost.com | MARCH 15, 2013

PAGE 21

FDA Update

velop and co-commercialize ibrutinib. The filing for ibrutinib in mantle cell lymphoma is expected to be made prior to the end of 2013, and discussions with the FDA about filing in Waldenstrom’s macroglobulinemia continue. The implications of Breakthrough Therapy :15.5” Designation cannot be determined at this time. The companies are working

with the FDA to determine any potential implications of the Breakthrough Therapy Designations to the ongoing and planned development activities. “As an oncology product, ibrutinib receiving the Breakthrough Therapy Designation is an example of progress and hope for patients fighting a range of cancers. This des-

ignation shows that the FDA is dedicated to using an ‘all hands on deck approach’ to work on products that show promise in treating serious and life-threatening diseases,” said Ellen Sigal, PhD, Chair and Founder of Friends of Cancer Research, a think tank and advocacy organization based in Washington, DC. “The break-

through pathway that our organization worked to create is intended to speed up the development and review of treatments that may demonstrate substantial improvement over existing therapies, and ibrutinib is a great example of using this new designation to potentially accelerate patient access to promising treatments.” n

ORAL, ONCE-DAILY THERAPY1

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1,3 Objective response rates (ORR) by IRF from ERIVANCE1,3* laBCC (n=63)

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

ORR (95% CI)

Median response duration (months) (95% CI)

*Patients received at least 1 dose of Erivedge with independent pathologist-conﬁrmed diagnosis of BCC. Response in laBCC: absence of disease progression and either ≥30% reduction in lesion size (sum of the longest diameter) from baseline in target lesions by radiography or in externally visible dimension (including scar tissue); or complete resolution of ulceration in all target lesions. Complete responders also had no residual BCC on sampling biopsy and partial responders had residual BCC on sampling biopsy. Response in mBCC: assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. IRF=Independent Review Facility. laBCC=locally advanced BCC. mBCC=metastatic BCC. CI=conﬁdence interval. NE=not estimable.

Adverse Reactions

• The most common adverse reactions (≥10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page.

See what you can offer your patients with advanced BCC at www.Erivedge.com References: 1. Erivedge® (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754. 3. Sekulic A, Migden MR, Oro AE, et al. N Engl J Med. 2012;366:2171-2179.

Trim:10.75”

Complete response

43% (n=27) (30.5-56.0) 21% (n=13)

mBCC (n=33) 30% (n=10) (15.6-48.2) 0%

The ASCO Post | MARCH 15, 2013

PAGE 22

FDA Update Myelodysplastic Syndromes

Apogenix Receives FDA Orphan Drug Designation for APG101 to Treat Myelodysplastic Syndromes and Initiates Clinical Phase I Study

pogenix GmbH, a biopharmaceutical company developing novel protein therapeutics for the treatment of cancer and inflammatory diseases,

announced that its lead compound, APG101 (Apocept), has been granted orphan drug designation from the FDA for the treatment of myelodysplastic synT:7”

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont) All aBCC Patients (N = 138) Grade 3 Grade 4 All Grades 3 (%) (%) (%) 1

MedDRA Preferred Term

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)].

All aBCC1 Patients (N = 138) MedDRA Preferred Term

Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). t "EWJTF QBUJFOUT UIBU &3*7&%(& FYQPTVSF EVSJOH QSFHOBODZ DBO cause embryo-fetal death or severe birth defects. t *OTUSVDU GFNBMF QBUJFOUT PG SFQSPEVDUJWF QPUFOUJBM UP VTF B IJHIMZ effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t *OTUSVDU BMM NBMF QBUJFOUT FWFO UIPTF XJUI QSJPS WBTFDUPNZ UP VTF condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ DPOUBDU UIFJS IFBMUIDBSF QSPWJEFS if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. t *OTUSVDU QBUJFOUT UP JNNFEJBUFMZ SFQPSU BOZ QSFHOBODZ FYQPTVSF UP ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. t *OGPSN GFNBMF QBUJFOUT PG UIF QPUFOUJBM GPS TFSJPVT BEWFSTF reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. t "EWJTF QBUJFOUT OPU UP EPOBUF CMPPE PS CMPPE QSPEVDUT XIJMF UBLJOH ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. t "EWJTF QBUJFOUT UP TXBMMPX &3*7&%(& DBQTVMFT XIPMF BOE OPU UP crush or open the capsules.

received orphan designation in the United States. With its novel mode of action, [APG101] restores the causal impairment of erythropoiesis in MDS. After the successful proof of concept in a randomized controlled trial in glioblastoma demonstrating excellent efficacy of [APG101] both in prolonging progression-free survival as well as overall survival, we are confident that the success story of [this agent] will continue….”

Phase I Trial

T:10”

1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients

dromes (MDS). Dr. Harald Fricke, COO/CMO of Apogenix, commented, “MDS is the second indication for which [APG101]

Simultaneously, Apogenix announced the initiation of a clinical phase I trial of APG101 in patients with MDS; the clinical trial is designed as an openlabel study and is conducted in clinical centers throughout Germany. Recruitment of subjects began in January 2013. Endpoints of the study include efficacy (improvement of erythropoiesis), safety, and tolerability parameters. Results of the trial are expected by mid-2014. APG101 binds to the CD95 ligand and blocks the activation of the CD95 receptor. Excessive stimulation of the CD95 receptor on hematopoietic cells present in the bone marrow of patients with MDS inhibits erythropoiesis. As a result, transfusion-dependent anemia develops, which is mostly refractory to erythropoiesis-stimulating agents. Preclinical studies using hematopoietic stem cells obtained from patients MDS show that APG101 dose-dependently stimulates erythropoiesis and thus may help treat anemia. n

The ASCO Post Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com. Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

ERIVEDGE ® [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0001559500 HED0000832301

Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

ASCOPost.com | MARCH 15, 2013

PAGE 23

Gastrointestinal Cancers Symposium Bevacizumab plus Capecitabine

reflects the population being treated, whose average age was 76.” Adverse events of special interest with bevacizumab included bleeding/ hemorrhage, which occurred in 25.4% of patients vs 6.6% with capecitabine, though grade 3 and higher toxicities were similar. Hypertension was more common in the combination group, but grade 3 and higher was observed in only 2.2%, vs 1.5% with capecitabine.

continued from page 1

The objective response rate was doubled, from 10.0% to 19.3% (P = .042), and the disease control rate was 74.3% with the combination vs 57.9% with = .005). A numericalmonotherapy (P �� ly longer overall survival was observed with bevacizumab—20.7 months vs 16.8 months—but this did not reach

Bevacizumab/Capecitabine in Colorectal Cancer ■■ In the international phase III AVEX trial, the addition of bevacizumab to

capecitabine in treatment-naive elderly colorectal cancer patients nearly doubled progression-free survival, with a trend toward improved survival.

■■ Patients receiving the combination had a median overall survival of almost 21 months.

■■ The combination was well tolerated. statistical significance (HR = 0.79; P = .182), Dr. Cunningham said. “Most people looking at the curve would be impressed by the trend favoring the combination, and a median survival of 20.7 months,” he commented. “Given the type of patients recruited, this is a worthwhile endeavor for the patients who receive it.” The study was powered to show a difference in progression-free but not overall survival, the authors noted.

Adverse Events Similar between Groups The combination group had greater study drug exposure, receiving a median of 5.8 cycles, vs 4.2 in the capecitabine arm. In spite of this, rates of any adverse event were similar between the groups, 95%. Grade 3 or 4 adverse events were more common with the combination than the single agent (59% vs 44.1%), but grade 5 adverse events were more common in patients receiving only capecitabine (11.8% vs 8.2%). Dr. Cunningham suggested that this high rate of grade 5 toxicity “probably

Venous and atrial thromboembolisms were also more common but grade 3 and higher events were rare. “The safety profile was consistent with previously reported data for bevacizumab in colorectal cancer,” he noted. “The combination is clearly effective, generally well tolerated, and in those over 70 results in meaningful disease control and good survival,” Dr. Cunningham maintained. “This is an international study, so the findings can be widely extrapolated.” n

EXPERT POINT OF VIEW

obert A. Wolff, MD, Professor in the Department of Gastrointestinal Oncology at The University of Texas MD Anderson Cancer Center, Houston, observed, “The bevacizumab seemed to leverage the capecitabine with a magnitude of benefit that is very reminiscent of the initial trials with irinotecan/5FU/leucovorin (IFL).” The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months with IFL plus placebo (HR = 0.66; P < .001), Hurwitz et al reported in 2004.2 “When we use oxaliplatin-containing regimens, we don’t see this leverage. The improvement in progression-free survival is quite modest when bevacizumab is added to a more active cytotoxic backbone,” he said. “Why do you get more leverage with a simpler cytotoxic plus bevacizumab?” Dr. Cunningham said the answer is unclear, but perhaps pairing bevacizumab with continuous (oral) dosing of the fluoropyrimidine is simply the optimal way to use the drug. He further suggested that the study population may be the optimal group for this combination. “Despite receiving only one line of therapy (only 37% received subsequent treatment),” he noted, overall survival was high even in the control group. “This may be a unique population” with relatively indolent disease, or perhaps the study selected a group for whom this combination is simply effective, he offered.

Earlier Data Confirmed Jordan Berlin, MD, Ingram Professor of Cancer Research and Clinical Director of the Gastrointestinal Oncology Program at Vanderbilt-Ingram Cancer Center, Nashville, seconded Dr. Wolff’s observations about the Hurwitz data. “This study confirms earlier data that fluoropyrimidine plus bevacizumab does have an interesting effect,” he said. The fact that the capecitabine-alone arm produced a median survival of almost 17 months also confirms previous studies that sug-

This study confirms earlier data that fluoropyrimidine plus bevacizumab does have an interesting effect.

Disclosure: Dr. Cunningham has received research funding from AstraZeneca, Merck, and Roche.

References 1. Cunningham D, Lang I, Lorusso V, et al: Bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer. 2013 Gastrointestinal Cancers Symposium. Abstract 337. Presented January 26, 2013. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.

—Jordan Berlin, MD

gested a subset of patients may be well off without aggressive therapy upfront, “for whom there is a benefit from treating with monotherapy and not necessarily going straight to doublets that are more toxic,” Dr. Berlin said. He reminded listeners, however, that patients with an abnormal glomerular filtration rate may be at risk for toxicity from capecitabine, which “could be an issue with the elderly.” n Disclosure: Dr. Berlin reported no potential conflicts of interest.

March Is

Colorectal Cancer Awareness Month.

6.7 months median PFS with INLYTA vs 4.7 months with sorafenib INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Important Safety Information Hypertension including hypertensive crisis has been observed. Gastrointestinal perforation and fistula, including death, have occurred. Blood pressure should be well controlled prior to initiating INLYTA. Use with caution in patients at risk for gastrointestinal perforation Monitor for hypertension and treat as needed. For persistent or fistula. Monitor for symptoms of gastrointestinal perforation or hypertension, despite use of antihypertensive medications, reduce fistula periodically throughout treatment. the dose. Discontinue INLYTA if hypertension is severe and persistent Hypothyroidism requiring thyroid hormone replacement has been despite use of antihypertensive therapy and dose reduction of reported. Monitor thyroid function before initiation of, and periodically INLYTA, and discontinuation should be considered if there is throughout, treatment. evidence of hypertensive crisis. Stop INLYTA at least 24 hours prior to scheduled surgery. Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk or Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue who have a history of these events. Hemorrhagic events, including fatal events, have been reported. treatment. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment.

INLYTA

for the treatment of advanced RCC after failure of one prior systemic therapy

PROOF OF SUPERIOR EFFICACY VERSUS SORAFENIB IN 2nd-LINE mRCC

IT MATTERS. Superior progression-free survival (PFS) vs sorafenib HR=0.67 (95% CI: 0.54, 0.81); P<.0001

Proportion progression-free

1.0 0.9

INLYTA (n=361)

6.7months (95% CI: 6.3, 8.6)

0.8

[43% longer median PFS]

0.7 0.6 0.5 0.4 0.3

Sorafenib (n=362)

4.7months (95% CI: 4.6, 5.6)

0.2 0.1 0.0

Time (months) Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimen). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 twice daily) with dose adjustments allowed in both groups.1

More than doubled objective response rate1 19.4% vs 9.4% with sorafenib –95% Cl: 15.4, 23.9 and 6.6, 12.9, respectively –Risk ratio: 2.06 (95% CI: 1.41, 3.00) All responses were partial responses per RECIST criteria

INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3 in vitro and in preclinical models Preclinical activity does not necessarily correlate with clinical outcomes

Liver enzyme elevation has been observed during treatment with INLYTA. Monitor ALT, AST, and bilirubin before initiation of, and periodically throughout, treatment. For patients with moderate hepatic impairment, the starting dose should be decreased. INLYTA has not been studied in patients with severe hepatic impairment. Women of childbearing potential should be advised of potential hazard to the fetus and to avoid becoming pregnant while receiving INLYTA. Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided. Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Please see brief summary on the following page.

The most common (≥20%) adverse events (AEs) occurring in patients receiving INLYTA (all grades, vs sorafenib) were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia, and constipation. The most common (≥10%) grade 3/4 AEs occurring in patients receiving INLYTA (vs sorafenib) were hypertension, diarrhea, and fatigue. The most common (≥20%) lab abnormalities occurring in patients receiving INLYTA (all grades, vs sorafenib) included increased creatinine, decreased bicarbonate, hypocalcemia, decreased hemoglobin, decreased lymphocytes (absolute), increased ALP, hyperglycemia, increased lipase, increased amylase, increased ALT, and increased AST.

Data are from a multicenter, open-label phase 3 trial of 723 patients with metastatic renal cell carcinoma (mRCC) after failure of 1st-line therapy (sunitinib-, temsirolimus-, bevacizumab-, or cytokine-containing regimens). Patients were randomized to either INLYTA (5 mg twice daily) or sorafenib (400 mg twice daily) with dose adjustments allowed in both groups. INLYTA® (AXITINIB) TABLETS FOR ORAL ADMINISTRATION Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE: INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended starting oral dose of INLYTA is 5 mg twice daily. Administer INLYTA doses approximately 12 hours apart with or without food. INLYTA should be swallowed whole with a glass of water. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Dose Modification Guidelines. Dose increase or reduction is recommended based on individual safety and tolerability. Over the course of treatment, patients who tolerate INLYTA for at least two consecutive weeks with no adverse reactions >Grade 2 (according to the Common Toxicity Criteria for Adverse Events [CTCAE]), are normotensive, and are not receiving anti-hypertension medication, may have their dose increased. When a dose increase from 5 mg twice daily is recommended, the INLYTA dose may be increased to 7 mg twice daily, and further to 10 mg twice daily using the same criteria. Over the course of treatment, management of some adverse drug reactions may require temporary interruption or permanent discontinuation and/or dose reduction of INLYTA therapy [see Warnings and Precautions]. If dose reduction from 5 mg twice daily is required, the recommended dose is 3 mg twice daily. If additional dose reduction is required, the recommended dose is 2 mg twice daily. Strong CYP3A4/5 Inhibitors: The concomitant use of strong CYP3A4/5 inhibitors should be avoided (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole). Selection of an alternate concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. Although INLYTA dose adjustment has not been studied in patients receiving strong CYP3A4/5 inhibitors, if a strong CYP3A4/5 inhibitor must be co-administered, a dose decrease of INLYTA by approximately half is recommended, as this dose reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve (AUC) to the range observed without inhibitors. The subsequent doses can be increased or decreased based on individual safety and tolerability. If co-administration of the strong inhibitor is discontinued, the INLYTA dose should be returned (after 3–5 half-lives of the inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor. Hepatic Impairment: No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). Based on the pharmacokinetic data, the INLYTA starting dose should be reduced by approximately half in patients with baseline moderate hepatic impairment (Child-Pugh class B). The subsequent doses can be increased or decreased based on individual safety and tolerability. INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). DOSAGE FORMS AND STRENGTHS 1 mg tablets of INLYTA: red, film-coated, oval tablets, debossed with “Pfizer” on one side and “1 XNB” on the other side. 5 mg tablets of INLYTA: red, film-coated, triangular tablets, debossed with “Pfizer” on one side and “5 XNB” on the other side. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Hypertension and Hypertensive Crisis. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard antihypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. Blood pressure should be well-controlled prior to initiating INLYTA. Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensive medications, reduce the INLYTA dose. Discontinue INLYTA if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis. If INLYTA is interrupted, patients receiving antihypertensive medications should be monitored for hypotension. Arterial Thromboembolic Events. In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident [see Adverse Reactions]. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. Venous Thromboembolic Events. In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism. Use INLYTA with caution in patients who are at risk for, or who have a history of, these events. INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. Hemorrhage. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib. INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose. Gastrointestinal Perforation and Fistula Formation. In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%). Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA. Thyroid Dysfunction. In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to *10 U/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib. Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state. Wound Healing Complications. No formal studies of the effect of INLYTA on wound healing have been conducted. Stop treatment with INLYTA at least 24 hours prior to scheduled surgery. The decision to resume INLYTA therapy after surgery should be based on clinical judgment of adequate wound healing. Reversible Posterior Leukoencephalopathy Syndrome. In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. There were two additional reports of RPLS in other clinical trials with INLYTA. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known. Proteinuria. In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib. Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib. Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, reduce the dose or temporarily interrupt INLYTA treatment.

AXU470817

Elevation of Liver Enzymes. In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm and 2% of patients on the sorafenib arm. Monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA. Hepatic Impairment. The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C). Pregnancy. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using INLYTA. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Women of childbearing potential should be advised to avoid becoming pregnant while receiving INLYTA. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of INLYTA has been evaluated in 715 patients in monotherapy studies, which included 537 patients with advanced RCC. The data described reflect exposure to INLYTA in 359 patients with advanced RCC who participated in a randomized clinical study versus sorafenib. The following risks, including appropriate action to be taken, are discussed in greater detail in other sections of the label: hypertension, arterial thromboembolic events, venous thromboembolic events, hemorrhage, gastrointestinal perforation and fistula formation, thyroid dysfunction, wound healing complications, RPLS, proteinuria, elevation of liver enzymes, and fetal development. Clinical Trials Experience. The median duration of treatment was 6.4 months (range 0.03 to 22.0) for patients who received INLYTA and 5.0 months (range 0.03 to 20.1) for patients who received sorafenib. Dose modifications or temporary delay of treatment due to an adverse reaction occurred in 199/359 patients (55%) receiving INLYTA and 220/355 patients (62%) receiving sorafenib. Permanent discontinuation due to an adverse reaction occurred in 34/359 patients (9%) receiving INLYTA and 46/355 patients (13%) receiving sorafenib. The most common (*20%) adverse reactions observed following treatment with INLYTA were diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, vomiting, asthenia, and constipation. The following table presents adverse reactions reported in *10% patients who received INLYTA or sorafenib. Adverse Reactions Occurring in *10% of Patients Who Received INLYTA or Sorafenib INLYTA

Sorafenib

(N=359)

Adverse Reaction

(N=355)

All Gradesb

Grade 3/4

All Gradesb

Grade 3/4

% 55 40 39 34 32 31 27 25 24 21 20 19 15 15 15 15 15 14 14 13 13 11 11 10 10 7 4 2

% 11 16 11 5 3 0 5 2 3 5 1 <1 1 1 2 1 3 2 1 1 <1 3 0 0 0 0 0 0

% 53 29 32 29 22 14 51 21 17 14 20 8 17 12 11 12 12 11 11 14 32 7 8 11 2 12 32 10

% 7 11 5 4 1 0 16 1 1 3 1 0 1 1 1 <1 3 1 0 1 4 2 0 0 0 0 0 <1

Diarrhea Hypertension Fatigue Decreased appetite Nausea Dysphonia Palmar-plantar erythrodysesthesia syndrome Weight decreased Vomiting Asthenia Constipation Hypothyroidism Cough Mucosal inﬂammation Arthralgia Stomatitis Dyspnea Abdominal pain Headache Pain in extremity Rash Proteinuria Dysgeusia Dry skin Dyspepsia Pruritus Alopecia Erythema

Percentages are treatment-emergent, all-causality events National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0

a b

Selected adverse reactions (all grades) that were reported in <10% of patients treated with INLYTA included dizziness (9%), upper abdominal pain (8%), myalgia (7%), dehydration (6%), epistaxis (6%), anemia (4%), hemorrhoids (4%), hematuria (3%), tinnitus (3%), lipase increased (3%), pulmonary embolism (2%), rectal hemorrhage (2%), hemoptysis (2%), deep vein thrombosis (1%), retinal-vein occlusion/thrombosis (1%), polycythemia (1%), transient ischemic attack (1%), and RPLS (<1%). The following table presents the most common laboratory abnormalities reported in *10% patients who received INLYTA or sorafenib. Laboratory Abnormalities Occurring in *10% of Patients Who Received INLYTA or Sorafenib Laboratory Abnormality Hematology Hemoglobin decreased Lymphocytes (absolute) decreased Platelets decreased White blood cells decreased Chemistry Creatinine increased Bicarbonate decreased Hypocalcemia ALP increased Hyperglycemia Lipase increased Amylase increased ALT increased AST increased Hypernatremia Hypoalbuminemia Hyperkalemia Hypoglycemia Hyponatremia Hypophosphatemia

INLYTA All Grade Gradesa 3/4 % %

Sorafenib All Grade Gradesa 3/4 % %

320 317 312 320

35 33 15 11

<1 3 <1 0

316 309 310 315

52 36 14 16

4 4 0 <1

336 314 336 336 336 338 338 331 331 338 337 333 336 338 336

55 44 39 30 28 27 25 22 20 17 15 15 11 13 13

0 <1 1 1 2 5 2 <1 <1 1 <1 3 <1 4 2

318 291 319 319 319 319 319 313 311 319 319 314 319 319 318

41 43 59 34 23 46 33 22 25 13 18 10 8 11 49

<1 0 2 1 2 15 2 2 1 1 1 3 <1 2 16

DRUG INTERACTIONS In vitro data indicate that axitinib is metabolized primarily by CYP3A4/5 and, to a lesser extent, CYP1A2, CYP2C19, and uridine diphosphate-glucuronosyltransferase (UGT) 1A1. CYP3A4/5 Inhibitors. Co-administration of ketoconazole, a strong inhibitor of CYP3A4/5, increased the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inhibitors should be avoided. Grapefruit or grapefruit juice may also increase axitinib plasma concentrations and should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended. If a strong CYP3A4/5 inhibitor must be coadministered, the INLYTA dose should be reduced [see Dosage and Administration]. CYP3A4/5 Inducers. Co-administration of rifampin, a strong inducer of CYP3A4/5, reduced the plasma exposure of axitinib in healthy volunteers. Co-administration of INLYTA with strong CYP3A4/5 inducers (e.g., rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and St. John’s wort) should be avoided. Selection of concomitant medication with no or minimal CYP3A4/5 induction potential is recommended [see Dosage and Administration]. Moderate CYP3A4/5 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma exposure of axitinib and should be avoided if possible. USE IN SPECIFIC POPULATIONS Pregnancy. Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies with INLYTA in pregnant women. INLYTA can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (*15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at *0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose). Nursing Mothers. It is not known whether axitinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INLYTA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. The safety and efficacy of INLYTA in pediatric patients have not been studied. Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at *15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at *5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatric Use. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were *65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were *65 years of age and younger. No dosage adjustment is required in elderly patients. Hepatic Impairment. In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B). No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C). Renal Impairment. No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min )creatinine clearance [CLcr] <89 mL/min). No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min). OVERDOSAGE There is no specific treatment for INLYTA overdose. In a controlled clinical study with INLYTA for the treatment of patients with RCC, 1 patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1). In a clinical dose finding study with INLYTA, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal hemoptysis. In cases of suspected overdose, INLYTA should be withheld and supportive care instituted. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies have not been conducted with axitinib. Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay. INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at *15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and *1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at *5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively). In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (*15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose). PATIENT COUNSELING INFORMATION Reversible Posterior Leukoencephalopathy Syndrome. Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances). Pregnancy. Advise patients that INLYTA may cause birth defects or fetal loss and that they should not become pregnant during treatment with INLYTA. Both male and female patients should be counseled to use effective birth control during treatment with INLYTA. Female patients should also be advised against breast-feeding while receiving INLYTA. Concomitant Medications. Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements. Rx only Issued: February 2012 Reference: 1. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939.

a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase

Selected laboratory abnormalities (all grades) that were reported in <10% of patients treated with INLYTA included hemoglobin increased (above the upper limit of normal) (9% for INLYTA versus 1% for sorafenib).

May 2012

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PAGE 27

Expert’s Corner

CancerLinQ continued from page 1

identified data from breast cancer patients’ electronic medical records into the CancerLinQ system, so the next step is to begin to measure these clinical experiences in relation to ASCO’s (and other high-level) breast cancer clinical practice guidelines and ASCO’s Quality Oncology Practice Initiative (QOPI®) measures. [Four large cancer centers—Maine Center for Cancer Medicine, Marin Specialty Care and Marin General Hospital (California), Space Coast Cancer Center (Florida), and Tennessee Oncology—and IntrinsiQ LLC, a leading source of U.S.-based oncology data and analysis, are providing anonymous case data on approximately 100,000 patients for inclusion in the CancerLinQ breast cancer prototype.] A critical point is that these patient records are being drawn from several widely used electronic medical records, emphasizing the ability of CancerLinQ to integrate medical information from many sources. Is there a timeline for when CancerLinQ will be ready for clinical practice? No, not yet, but we are making rapid progress. We are learning many lessons from the prototype. The next steps include accepting prototype data from additional sites. We are also building the data governance, privacy, and security standards for the full CancerLinQ system.

Program Capabilities Will CancerLinQ have the ability to capture all the pertinent information about a patient, including molecular characteristics of the patient’s tumor, and then determine the most effective treatment options? We hope the information the system will capture is even broader than that. The idea is to include all of the relevant information about a specific patient, which could include genomics, but it doesn’t have to in all situations. The CancerLinQ rapid learning system can also include any standard testing and testing yet to be developed that may be used in the future. It includes demographic information about patients, classic anatomic pathology reports, concurrent medications, and other illnesses the patient

may have. Ultimately, the system should also include an assessment of the patient’s toxicity risk tolerance and goals of care. There really is no limit to the kinds of medical information that might be included to allow ever more precise feedback and guidance in the form of clinical-decision support. But, yes, CancerLinQ will certainly include more and more genomic data primarily as a response to its demonstrated everyday utility, but eventually perhaps to contribute information that may aid in the exploration of important associations between specific genomic patterns and treatment and disease outcomes.

decisions and to also recognize factors that may have been omitted. A very simple example would be, if a patient has early-stage ER-positive breast cancer and there are no prescriptions for hormonal therapy entered into her electronic medical record, CancerLinQ would recognize that there was an omission and question why. Or more simply, it might say, “No prescription has been given for tamoxifen.” Then the physician might type in, “The patient has a specific contraindication and can’t take tamoxifen.” It is important to emphasize that CancerLinQ is really just delivering the current standards in a faster, more

[CancerLinQ] will include clinical decision-support technology that helps physicians identify the factors they need to make evidence-based treatment decisions. —Clifford A. Hudis, MD

I think it helps to take a half-step back and recognize that these factors—and more—are the things that a physician would use to make some assessments about the best therapeutic approach for a patient. But in the end, this system is never going to treat a patient. It will look at a patient’s situation and determine what the standard therapy is to consider. If the physician elects to treat in a different fashion, the system will provide an alert detailing how he or she might be deviating from what is expected. But then it is still up to the doctor to be a doctor and, with the patient, determine the best course of care. Similarly, the system might inform the doctor about a research opportunity that the doctor might want to consider for the patient. This has the exciting potential to both maintain high quality of care independent of geography and to increase the efficiency of clinical trials.

Decision-making Potential Will CancerLinQ have the potential to make the treatment decision-making process more precise? It will include clinical decisionsupport technology that helps physicians identify the factors they need to make evidence-based treatment

efficient fashion. It is not ever replacing sound medical judgment and responsibility. It also sounds like CancerLinQ has the potential to provide a greater opportunity for shared decision-making between the physician and patient. That could be. Overall, the opportunity is for a better sharing and distribution of knowledge. Physicians don’t have to be at an academic or research center in order to be aware of the most recent treatment developments. An example might be an oncologist seeing a patient who is 5½ years from diagnosis and has been on tamoxifen for 5 years. A few weeks ago the oncologist might have said, “You are done with treatment” and sent that patient for routine followup. If operational today, CancerLinQ could have provided information showing that a study presented at the most recent San Antonio Breast Cancer Symposium found that 10 years vs 5 years of tamoxifen has a survival advantage. Without having traveled to the meeting, this oncologist could be made aware of this finding to consider in the treatment of her patient today. There are myriad other examples, of course.

Cost Considerations Do you know how expensive CancerLinQ will be for oncology practices and hospitals to adopt? That’s a complicated question, because the actual computer network system is very expensive to build. But physician practices and cancer centers are already making investments in the creation of their own electronic medical records, so at the practice level there is not much more of an investment needed to implement this system. CancerLinQ will be broadly compatible with existing electronic medical records, so it should not be a prohibitive expense at the practice level. In the end, it will have to offer our community an acceptable return on investment or it will not succeed.

Looking Ahead Your term as ASCO President begins in June. What are some of your expectations, in terms of challenges and goals? The one thing I’ve been consistently warned about by everybody is that whatever I think the challenges are, other things will happen that I don’t anticipate. My goals, of course, include the continuing rapid deployment and maturation of CancerLinQ. For the longer term, one of the most critical issues for us is going to be the completion of an anonymized data set from the electronic medical records of the breast cancer patients for the CancerLinQ prototype and our ability to mine that data and use it productively. That is why I think the implementation of CancerLinQ is so important. It isn’t just about having access to thousands of electronic medical records locked away in academic centers and oncology offices across the country. It is also having the ability to provide real-time, standardized, clinical decision-support tools built into the system, as well as other value-added tools, including QOPI performance measures. It is the potential of CancerLinQ to transform the way cancer is understood and treated that I think is so important about the technology. n

Disclosure: Dr. Hudis reported no potential conflicts of interest.

The ASCO Post | MARCH 15, 2013

PAGE 28

News

Obesity, Physical Inactivity Linked with Risk for Subtype of Colorectal Cancer

n increasing body mass index (BMI) was associated with a higher risk for colorectal cancer with a specific molecular characteristic, and inversely, physical activity was linked to a decreased risk for that same cancer,

according to data published in Cancer Research,1 a journal of the American Association for Cancer Research. “We know that exercise and avoiding obesity decrease colorectal cancer risk, but little is known about why,” said one

of the study authors, Shuji Ogino, MD, PhD, Associate Professor of Pathology at Dana-Farber Cancer Institute and Associate Professor in the Department of Epidemiology at Harvard School of Public Health in Boston. “In this study,

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we used a biomarker named CTNNB1, which is a molecule implicated in cancer and obesity, to divide patients into two groups, CTNNB1-positive and CTNNB1-negative.”

Study Details Dr. Ogino and colleagues used data from more than 100,000 women from the Nurses’ Health Study and more than 45,000 men in the Health Professionals Study to examine whether there was an association between BMI or exercise activity and colorectal cancer risk according to CTNNB1 expression status. Among the study population, 2,263 individuals were diagnosed with colorectal cancer during follow-up. Tumor CTNNB1 expression data were available for 861 of these individuals, and 54% of these tumors were negative for CTNNB1 and 46% positive for the biomarker.

Results Increasing BMI by a 5.0 kg/m2 increment was associated with a 34% higher risk for CTNNB1-negative cancer, but was not associated with CTNNB1positive cancer. In contrast, increasing physical activity level was associated with a significantly lower risk for CTNNB1-negative cancer. It was not associated with CTNNB1-positive cancer. “Our results provide additional evidence for a causal role of obesity and a physically inactive lifestyle in a specific molecular subtype of colorectal cancer,” Dr. Ogino said. The data also indicated that CTNNB1 could be a potential target for chemoprevention and treatment, said Dr. Ogino. He called for more population-based, large-scale databases to facilitate molecular pathological epidemiology research. “Currently, most population-based studies do not take tumor heterogeneity into consideration, and typically colon cancer is treated as a single disease,” he said. “We need to integrate molecular pathology and epidemiology in education and research to facilitate integrative science and improve public health.” n Reference 1. Morikawa T, Kuchiba A, Lochhead P, et al: Cancer Res. February 26, 2013 (early release online).

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Perspective

A Better Doctor continued from page 1

Recurrence

Since then, I’ve been on a cancerrecurrence whirlwind and it’s hard for me to remember the sequence of events and numerous treatments I’ve had. I know that a year after my diagnosis, the cancer metastasized to my abdominal wall, then to my small bowel, and a year after that to the mesentery, which required significant removal of my small intestine. I’ve also had surgery to remove my gall bladder. I’ve lost the exact count, but I think in all I’ve had six recurrences—the last, a year ago—and nine surgeries. In addition to the numerous surgeries, I’ve also been treated with radiation and bombarded with a series of highdose chemotherapeutics—fluorouracil, oxaliplatin, leucovorin, irinotecan, bevacizumab (Avastin), and cetuximab (Erbitux)—so lethal, they nearly killed me.

Medicine Is My Salvation Through it all, I never missed more than 3 weeks of work. Medicine is my salvation and it has kept me sane. Although I don’t delude myself about the serious situation I am in, I never see myself as someone who is not going

to get better. My attitude is, whatever happens, happens, and while I hope I get better, during my remissions I try not to think about my cancer. Recently, I participated in a proj-

survivorship and go back to my life as David Posner, MD. What has helped me get through the past decade is to pretend I don’t have cancer. I know my colorectal cancer has a chance of recur-

It is unconscionable to me that any patient is allowed to linger for days and sometimes weeks in a state of uncertainty, in some cases waiting to learn whether they will live or die. —David Posner, MD

ect launched by The New York Times that asked cancer survivors to submit their personal stories. The result is the new book Picture Your Life After Cancer (American Cancer Society, 2012). I also participated in a seminar the Times held on cancer survivorship and met a breast cancer survivor whose life revolves so much around having cancer, she’s planned her funeral with the same kind of meticulous detail other people reserve for their wedding. It was then that I decided to relinquish my role as poster child for cancer

ring, but if I spend all my time thinking about that, I wouldn’t be able to live the life I love being a doctor.

Cancer Has Made Me a Better Doctor While I’ve always considered myself a caring and empathetic physician, having a life-threatening disease has given me new insight into the terror patients with serious diseases often feel, and it has made me a better doctor. Knowing the anguish of waiting for test results that would give me ei-

ther another 6 months of reprieve from cancer or immediately send me back to the operating table or chemotherapy infusion room, has made me vow to never let my patients finish their day without knowing the results from their PET scan or other tests performed that morning. Because I have a busy pulmonary practice, if a patient’s test results are negative, my assistant will call to deliver the news, and if the results are positive, I call. It is unconscionable to me that any patient is allowed to linger for days and sometimes weeks in a state of uncertainty, in some cases waiting to learn whether they will live or die. The fact that I look so healthy despite all my treatment and that I’m a 10-year survivor of colorectal cancer is comforting to my patients with cancer. And because I recognize their look of distress so well, I’m able to offer credible reassurance that what they are feeling is natural. Most of all, having cancer has given me the ability to alter the way I interact with patients based on their individual circumstance and need. And in return, I get to pretend I don’t have cancer—at least for a while. n Disclosure: Dr. Posner reported no potential conflicts of interest.

Don’t Miss These Important Reports in this Issue of The ASCO Post Matthew R. Smith, MD, PhD, on ARN-509 in Prostate Cancer see page 7

Neal J. Meropol, MD, on Second-line Targeted Therapy in Gastric Cancer see page 10

Ian W. Flinn, MD, PhD, on Bendamustine/Rituximab in NHL and MCL see page 31

Mark J. Levis, MD, on Quizartinib in Acute Myeloid Leukemia see page 33

Lynn D. Wilson, MD, MPH, FASTRO, on Palliative Radiotherapy for NSCLC see page 36

J. Randolph Hecht, MD, on HER2 Status in Esophageal Cancers see page 59

Seema A. Khan, MD, on Sentinel Node Surgery in Node-positive Breast Cancer see page 68

Robert A. Moss, MD, FACP, on the Medical Oncology Association of Southern California see page 108

Nancy L. Keating, MD, MPH, on Multidisciplinary Tumor Boards see page 110

Visit The ASCO Post online at ASCOPost.com

The ASCO Post | MARCH 15, 2013

PAGE 30

In the Clinic Hematology

Pomalidomide in Previously Treated Multiple Myeloma By Matthew Stenger

In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

n February 8, 2013, the immunomodulatory agent pomalidomide (Pomalyst) was granted accelerated approval for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide (Revlimid) and bortezomib (Velcade) and who showed disease progression within 60 days of completion of their last therapy.1 Approval was based on response rate. Improvement in survival or symptoms with pomalidomide treatment has not yet been verified. Due to embryo-fetal risk associated with pomalidomide treatment, the drug is available only through a restricted distribution program. The approval was based on the results of a multicenter, randomized, open-label study (CC-4047-MM-002) in which 221 patients with relapsed/refractory multiple myeloma who had previously re-

OF NOTE Pomalidomide enhances T cell– and natural killer cell–mediated immunity and inhibits monocyte production of proinflammatory cytokines, inhibiting proliferation and inducing apoptosis of hematopoietic tumor cells. ceived lenalidomide and bortezomib and who were refractory to the last myeloma therapy were randomized to pomalidomide alone (n�� =�� 108) alone or pomalidomide plus low-dose dexamethasone (n = 113).2 Dexamethasone was added to treatment in 61 patients in the pomalidomide-alone group. Due to risk of venous thromboembolism with pomalidomide, all patients were required to receive prophylaxis or antithrombotic treatment. For the pomalidomide and pomalidomide-plus-dexamethasone groups, respectively, median ages were 61 years (40% ≥ 65 years) and 64 years (47% ≥ 65 years), 53% and 55% were male, 80%

and 81% were white, 88% and 88% had ECOG performance status of 0 or 1, median number of prior therapies was 5 and 5, 76% and 74% had prior transplantation, and 59% and 61% were refractory to bortezomib and lenalidomide. The overall response rate was 7% with pomalidomide alone and 29% with pomalidomide plus low-dose dexamethasone, with one complete response observed in the latter group. Median duration of response was not reached in the pomalidomide group and was 7.4 months among patients receiving pomalidomide plus low-dose dexamethasone. As a condition of the accelerated

on days 1 to 21 of 28-day cycles repeated until disease progression. It may be given in combination with dexamethasone. It should be taken without food. No cycle of pomalidomide should be started in patients with a neutrophil count less than 500/µL or platelet count less than 50,000/µL. For neutropenia and thrombocytopenia, pomalidomide treatment should be interrupted and reinitiated at 3 mg upon resolution for the first episode and at 1 mg lower than the preceding dose for any subsequent episodes. For other grade 3 or 4 toxicities, treatment should be interrupted until recovery and then resumed at a dose

Pomalidomide to Treat Multiple Myeloma ■■ Pomalidomide (Pomalyst) has been approved for the treatment of

patients with multiple myeloma who have received at least two prior therapies including lenalidomide (Revlimid) and bortezomib (Velcade) and who showed disease progression within 60 days of completing their last therapy.

■■ Pomalidomide is given orally at 4 mg/d on days 1 to 21 of 28-day cycles repeated until disease progression.

approval, FDA requires submission of the results of a randomized clinical trial (CC-4047-MM-007) of pomalidomide added to bortezomib and low-dose dexamethasone compared to bortezomib plus low-dose dexamethasone in previously treated multiple myeloma.

How It Works Pomalidomide, which is an analog of thalidomide, is an immunomodulatory agent with antineoplastic activity. The agent enhances T cell– and natural killer cell–mediated immunity and inhibits monocyte production of proinflammatory cytokines (eg, tumor necrosis factor-alpha and interleukin-6). It has shown antiangiogenic activity in animal tumor models and in vitro in the umbilical cord model. In cellular assays, pomalidomide inhibits proliferation and induces apoptosis of hematopoietic tumor cells. It has been found to inhibit proliferation of lenalidomide-resistant multiple myeloma cell lines and to exhibit synergistic activity in inducing apoptosis when combined with dexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines.

How It Is Given The recommended starting dose of pomalidomide is 4 mg once daily orally

1 mg lower than the preceding dose.

REMS Thalidomide (Thalomid) is a known human teratogen that causes severe birth defects or embryo-fetal death. Due to embryo-fetal risk with pomalidomide, it is available only through a restricted program under a risk evaluation and mitigation strategy called POMALYST REMS. Prescribers and pharmacies dispensing the drug must be certified with this program, and patients must sign a patient-prescriber agreement form in order to receive pomalidomide. (Information about the POMALYST REMS program is available at celgeneriskmanagement.com or at 1-888-423-5436.) Pomalidomide is contraindicated in pregnant women, and women of reproductive potential must avoid pregnancy while taking the drug and for at least 4 weeks after completing therapy. Women of reproductive potential must use two reliable methods of contraception starting 4 weeks before treatment and continuing through 4 weeks after final discontinuation of treatment. Two negative pregnancy tests must be obtained prior to initiating therapy. Since pomalidomide is present in semen, men must always use a latex or synthetic condom during any sexual

OF NOTE Pomalidomide carries boxed warnings for embryo-fetal toxicity, use only through the POMALYST REMS program, and venous thromboembolism. contact with women of reproductive potential while taking pomalidomide and for up to 28 days after discontinuing treatment, even if they have undergone a successful vasectomy. Patients receiving pomalidomide must not donate blood during treatment or for 1�� month following treatment.

How It Is Metabolized Pomalidomide is primarily metabolized by CYP1A2 and CYP3A, and it is a substrate for P-glycoprotein. Coadministration of pomalidomide with strong inhibitors of CYP1A2 (eg, ciprofloxacin, enoxacin, fluvoxamine), CYP3A (eg, clarithromycin, ketoconazole, grapefruit juice), or Pglycoprotein (eg, azithromycin, amiodarone, itraconazole) could increase pomalidomide exposure and should be avoided. Likewise, strong inducers of CYP1A2 (eg, broccoli, modafinil, nafcillin), CYP3A (eg, carbamazepine, phenytoin, rifampin), or P-glycoprotein (eg, avasimibe, rifampin, St. John’s wort) could decrease pomalidomide exposure and should be avoided. Cigarette smoking may reduce pomalidomide exposure via CYP1A2 induction, and patients should be advised that smoking may thus reduce the efficacy of pomalidomide.

Safety Profile Patients in the clinical trial received a median of five cycles of treatment. Overall, the most common adverse events of any grade were fatigue and asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infection, back pain, and pyrexia. The most common grade 3 or 4 adverse events in the pomalidomidealone and pomalidomide-plus-dexamethasone groups were neutropenia (47% and 38%), anemia (22% and 21%), thrombocytopenia (22% and 19%), pneumonia (16% and 23%), continued on page 31

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

now indicated in combination with carboplatin for the first-line treatment of advanced Non–Small Cell lung Cancer

Scan with your mobile device to learn more at www.abraxane.com

Please see Important Safety Information for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on adjacent pages, and Brief Summary on following pages.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non–small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1,500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 for metastatic breast cancer (MBC) and Days 1, 8, and 15 for non-small cell lung cancer (NSCLC) • Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3 • In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC • In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 • In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1,500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for MBC or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • The starting dose should be reduced for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood

Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS Randomized Metastatic Breast Cancer (MBC) Study • The most common adverse reactions (≥20%) with single-agent use of ABRAXANE in the MBC study were alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), abnormal ECG (all patients 60%; patients with normal baseline 35%), fatigue/ asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), AST elevation (any 39%), alkaline phosphatase elevation (any 36%), anemia (all cases 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%) and infections (24%) • Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients • Other adverse reactions of note included vomiting (any 18%; severe 4%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%); mucositis (any 7%; severe <1%), hepatic dysfunction (elevations in bilirubin 7%), hypersensitivity reactions (any 4%; severe 0%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In all ABRAXANE treated patients (n=366) ocular/visual disturbances were reported (any 13%; severe 1%). Dehydration and pyrexia were also reported • Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients and included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension • Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported Non-Small Cell Lung (NSCLC) Cancer Study • Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin in NSCLC were anemia (28%); neutropenia (47%); thrombocytopenia (18%), and peripheral neuropathy (3%) • The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin for NSCLC were anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue • The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC were anemia (4%) and pneumonia (3%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%) • The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%)

Please see Brief Summary for ABRAXANE, including Boxed WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on following pages.

• The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%) • The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group) Post-marketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or to human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated Geriatric • No toxicities occurred notably more frequently among patients ≥65 years of age who received ABRAXANE for MBC • Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Dose adjustment is recommended for patients with moderate and severe hepatic impairment and patients who experience severe neutropenia or severe sensory neuropathy during treatment with ABRAXANE • Withhold ABRAXANE if AST >10 x ULN or bilirubin >5 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicities • Monitor patients closely

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary; refer to full prescribing information for complete product information. WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.1, 6.2)]. • Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer ABRAXANE is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. 1.2 Non-Small Cell Lung Cancer ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. 2 DOSAGE AND ADMINISTRATION 2.1 Metastatic Breast Cancer After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. 2.2 Non-Small Cell Lung Cancer The recommended dose of ABRAXANE is 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. The recommended dose of carboplatin is AUC = 6 mg•min/mL on Day 1 only of each 21-day cycle, beginning immediately after the completion of ABRAXANE administration. 2.3 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1. For metastatic breast cancer, the dose of ABRAXANE can be increased from 130 mg/m2 up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. For non-small cell lung cancer, reduce the dose of ABRAXANE to 50 mg/m2 in patients with severe hepatic impairment. In subsequent cycles, the dose of ABRAXANE may be increased to 75 mg/m2 as tolerated. Monitor patients closely [see Warnings and Precautions (5.4), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin Levels ABRAXANE Dosea Levels MBC NSCLC Mild < 10 x ULN > ULN to ≤ 1.25 x ULN 260 mg/m2 100 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN 200 mg/m2 75 mg/m2 Severe < 10 x ULN 2.01 to 5 x ULN 130 mg/m2 b 50 mg/m2 c > 10 x ULN OR > 5 x ULN not eligible not eligible MBC = Metastatic Breast Cancer; NSCLC = Non-Small Cell Lung Cancer. a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance. c Increase dose to 75 mg/m2 in subsequent courses, as tolerated. 2.4 Dose Reduction/Discontinuation Recommendations Metastatic Breast Cancer Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For Grade 3 sensory neuropathy hold treatment until resolution to

Grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1, 5.2) and Adverse Reactions (6.1)]. Non-Small Cell Lung Cancer • Do not administer ABRAXANE on Day 1 of a cycle until absolute neutrophil count (ANC) is at least 1500 cells/mm3 and platelet count is at least 100,000 cells/mm3 [see Contraindications (4),Warnings and Precautions (5.1) and Adverse Reactions (6.2)]. • In patients who develop severe neutropenia or thrombocytopenia withhold treatment until counts recover to an absolute neutrophil count of at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an absolute neutrophil count of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle. Upon resumption of dosing, permanently reduce ABRAXANE and carboplatin doses as outlined in Table 2. • Withhold ABRAXANE for Grade 3-4 peripheral neuropathy. Resume ABRAXANE and carboplatin at reduced doses (see Table 2) when peripheral neuropathy improves to Grade 1 or completely resolves [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]. Table 2: Permanent Dose Reductions for Hematologic and Neurologic Adverse Drug Reactions in NSCLC Weekly Every 3-Week Adverse Drug Reaction Occurrence ABRAXANE Dose Carboplatin Dose 2 (mg/m ) (AUC mg•min/mL) Neutropenic Fever (ANC less than 500/mm3 First 75 4.5 with fever >38°C) OR Delay of next cycle by more than 7 days for ANC Second 50 3 less than 1500/mm3 OR Third Discontinue Treatment ANC less than 500/mm3 for more than 7 days First 75 4.5 Platelet count less than 50,000/mm3 Second Discontinue Treatment First 75 4.5 Severe sensory Neuropathy – Second 50 3 Grade 3 or 4 Third Discontinue Treatment 4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC) and 47% of patients with non-small cell lung cancer (NSCLC). Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with either MBC or NSCLC. In patients with MBC, resume treatment with every-3-week cycles of ABRAXANE after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In patients with NSCLC, resume treatment if recommended (see Dosage and Administration, Table 2) at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle [see Dosage and Administration (2.4)]. 5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions (6.1, 6.2)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, treatment should be withheld until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.4)]. 5.3 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience

a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug. 5.4 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.5 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. 5.6 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations. There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)]. 5.7 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)]. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (â&#x2030;Ľ 20%) with single-agent use of ABRAXANE in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea [see Adverse Reactions (6.1)]. The most common adverse reactions (â&#x2030;Ľ 20%) of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue [see Adverse Reactions (6.2)] The most common serious adverse reactions of ABRAXANE in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%). The most common adverse reactions resulting in dose reduction of ABRAXANE were neutropenia (24%), thrombocytopenia (13%), and anemia (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing were neutropenia (41%), thrombocytopenia (30%), and anemia (16%). 6.1 Clinical Trials Experience in Metastatic Breast Cancer Table 3 shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE or paclitaxel injection for the treatment of metastatic breast cancer. Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 (continued)

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Metastatic Breast Cancer Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE Paclitaxel Injection 260 mg/m2 over 30 min 175 mg/m2 over 3 hb (n=229) (n=225) Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactionc All 4 12 Severed 0 2 Cardiovascular Vital Sign Changes During Administration Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsd 3 4 Abnormal ECG All Patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsd 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsd 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsd 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsd 0 <1 Gastrointestinal Nausea Any Symptoms 30 22 Severe Symptomsd 3 <1 Vomiting Any Symptoms 18 10 Severe Symptomsd 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsd <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsd <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 2. b Paclitaxel injection patients received premedication. c Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. d Severe events are defined as at least grade 3 toxicity. Adverse Event Experiences by Body System Hematologic Disorders Neutropenia was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose

of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. Pancytopenia has been observed in clinical trials. Infections Infectious episodes were reported in 24% of the patients treated with ABRAXANE. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Hypersensitivity Reactions (HSRs) Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients. These events included cardiac ischemia/infarction, chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Dyspnea (12%), cough (7%), and pneumothorax (<1%) were reported after treatment with ABRAXANE. Neurologic The frequency and severity of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients. Twenty-four patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No Grade 4 sensory neuropathies were reported. Only one incident of motor neuropathy (Grade 2) was observed in either arm of the controlled trial. Vision Disorders Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. Arthralgia/Myalgia The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Other Clinical Events Nail changes (changes in pigmentation or discoloration of nail bed) have been reported. Edema occurred in 10% of patients; no patients had severe edema. Dehydration and pyrexia were also reported. 6.2 Clinical Trials Experience in Non-Small Cell Lung Cancer Adverse reactions were assessed in 514 ABRAXANE/carboplatin-treated patients and 524 paclitaxel injection/carboplatin-treated patients receiving first-line systemic treatment for locally advanced (stage IIIB) or metastatic (IV) non-small cell lung cancer (NSCLC) in a multicenter, randomized, open-label trial. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. The differences in paclitaxel dose and schedule between the two arms limit direct comparison of dose- and schedule-dependent adverse reactions. Among patients evaluable for adverse reactions, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma,

43% had squamous cell lung cancer, 76% were ECOG PS 1. Patients in both treatment arms received a median of 6 cycles of treatment. The following common (≥ 10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia 56%, nausea 27%, fatigue 25%, decreased appetite 17%, asthenia 16%, constipation 16%, diarrhea 15%, vomiting 12%, dyspnea 12%, and rash 10% (incidence rates are for the ABRAXANE plus carboplatin treatment group). Table 4 provides the frequency and severity laboratory-detected abnormalities which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 toxicity between ABRAXANE plus carboplatin-treated patients or paclitaxel injection plus carboplatin-treated patients. Table 4: Selected Hematologic Laboratory-Detected Abnormalities With a Difference of ≥ 5% for grades (1-4) or ≥ 2% for Grade 3-4 Toxicity Between Treatment Groups ABRAXANE Paclitaxel Injection (100 mg/m2 weekly) (200 mg/m2 every 3 weeks) plus carboplatin plus carboplatin Grades Grade Grades Grade 1-4 (%) 3-4 (%) 1-4 (%) 3-4 (%) Anemia1,2 98 28 91 7 Neutropenia 1,3 85 47 83 58 Thrombocytopenia1,3 68 18 55 9 1 508 patients assessed in ABRAXANE/carboplatin-treated group 2 514 patients assessed in paclitaxel injection/carboplatin-treated group 3 513 patients assessed in paclitaxel injection/carboplatin-treated group Table 5 provides the frequency and severity of adverse reactions, which occurred with a difference of ≥ 5% for all grades (1-4) or ≥ 2% for Grade 3-4 between either treatment group for the 514 ABRAXANE plus carboplatin-treated patients compared with the 524 patients who received paclitaxel injection plus carboplatin. Table 5: Selected Adverse Reactions with a Difference of ≥5% for All Grade Toxicity or ≥2% for Grade 3-4 Toxicity Between Treatment Groups Paclitaxel Injection ABRAXANE (200 mg/m2 2 (100 mg/m weekly) every 3 weeks) + carboplatin (N=514) + carboplatin (N=524) MedDRA Grade 1-4 Grade 3-4 Grades 1-4 Grade 3-4 System Organ v 12.1 Toxicity Toxicity Toxicity Toxicity Class Preferred Term (%) (%) (%) (%) Nervous system Peripheral 48 3 64 12 disorders neuropathya General Edema 10 0 4 <1 disorders and peripheral administration site conditions 7 0 2 0 Respiratory Epistaxis thoracic and mediastinal disorders Musculoskeletal Arthralgia 13 <1 25 2 and connective 10 <1 19 2 tissue disorders Myalgia a Peripheral

neuropathy is defined by the MedDRA Version 14.0 SMQ neuropathy (broad scope). For the ABRAXANE plus carboplatin treated group, 17/514 (3%) patients developed Grade 3 peripheral neuropathy and no patients developed Grade 4 peripheral neuropathy. Grade 3 neuropathy improved to Grade 1 or resolved in 10/17 patients (59%) following interruption or discontinuation of ABRAXANE. 6.3 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy. Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord par esis have been reported, as well as autonomic neuropathy resulting in paralytic ileus. Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline. Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration. Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported. Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia. Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection. 6.4 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. 7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4. There are no clinically important pharmacokinetic drug-drug interactions between carboplatin and ABRAXANE [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.6)]. There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received ABRAXANE. Of the 514 patients in the randomized study who received ABRAXANE and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old. 8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment. 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton. 16.2 Storage Store the vials in original cartons at 20°C to 25°C (68° F to 77°F). Retain in the original package to protect from bright light. 16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1)]. • Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.7)]. • Patients must be informed of the risk of low blood cell counts and instructed to contact their physician immediately for fever or evidence of infection. • Patients should be instructed to contact their physician for persistent vomiting, diarrhea, signs of dehydration, cough or breathing difficulties, or signs of an allergic reaction. • Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)]. • Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE. • Patients must be informed that hypersensitivity reactions may occur, which could be severe and sometimes fatal. Manufactured for: Celgene Corporation Summit, NJ 07901 ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2012 Abraxis BioScience, LLC. All Rights Reserved. Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006; 7,820,788; 7,923,536; 8,034,375; 8,268,348; and RE41,884. ABRPI.004/PPI.004 10/12

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News Hematology

Bendamustine/Rituximab Noninferior to Standard Chemotherapy for Advanced Indolent Non-Hodgkin and Mantle Cell Lymphomas By Alice Goodman

he combination of bendamustine (Treanda) and rituximab (Rituxan), or BR, was found to be noninferior to commonly used chemotherapy with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) in patients with previously untreated advanced indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL) in the randomized phase III BRIGHT trial reported at the 2012 American Society of Hematology (ASH) Annual Meeting.1 Nevertheless, BR and R-CHOP/R-CVP have distinct toxicity profiles, which should be considered in treatment selection.

Important Option “The overall response rate was high in both treatment groups. BR is an important treatment option for previously untreated indolent NHL and MCL,” stated lead author Ian W. Flinn, MD, PhD, Director of the Hematologic Malignancies Program at Sarah Cannon Research Institute, Nashville. “There is no single standard ther-

The overall response rate was high in both treatment groups. BR is an important treatment option for previously untreated indolent NHL and MCL. —Ian W. Flinn, MD, PhD

apy for indolent NHL or MCL,” Dr. Flinn continued. The present study sought to evaluate BR, which is becoming a standard in Germany. The StiL NHL study, reported last year, showed a large difference in progression-free survival in patients with follicular NHL and MCL, favoring BR over R-CHOP (at a median follow-up of 45 months, median progressionfree survival was 69.5 months for BR vs 31.2 months for R-CHOP).2 A survey presented at this year’s ASH 2012 meeting showed that BR is replacing R-CHOP in Germany for treatment of indolent lymphoma.3 The BRIGHT study was done to see if the advantage of the StiL trial could be confirmed.

Role of Bendamustine/Rituximab in Lymphoma ■■ In a study designed for FDA review, bendamustine/rituximab (BR)

demonstrated noninferiority to R-CHOP/R-CVP for advanced follicular lymphoma, based on complete response rates.

■■ The complete response rate for mantle cell lymphoma was significantly higher for BR than for R-CHOP/R-CVP (51% vs 24%, P = .02).

Pomalidomide continued from page 30

fatigue and asthenia (11% and 13%), back pain (12% and 9%), and dyspnea (7% and 13%). Serious adverse events occurred in 67% of the pomalidomide-alone group and 62% of the pomalidomide-plusdexamethasone group, with the most common being pneumonia (14% and 19%), renal failure (8% and 6%), and dyspnea (5% and 6%). Overall, dose interruption and dose reduction of either drug due to adverse events occurred in 63% and 37% of patients, respectively, and discontinuation of treatment due to treatment-related ad-

verse events occurred in 3%. Among adverse events of particular interest with pomalidomide, deep-vein thrombosis or pulmonary embolism occurred in 3% of patients, dizziness occurred in 18% of patients (grade 3/4 in 1%) and confusional state in 12% (grade 3/4 in 3%), and neuropathy occurred in 18% (all grade 1/2), including peripheral neuropathy in 9%. Pomalidomide carries boxed warnings for embryo-fetal toxicity, use only through the POMALYST REMS program, and venous thromboembolism. It also has warnings/precautions for hematologic toxicity, hypersensitivity re-

Study Design BRIGHT used complete response as the primary endpoint, and showed no difference between the two treatment arms. Dr. Flinn said that progression-free survival is a more clinically meaningful endpoint than complete response but explained that BRIGHT was designed for an FDA application and is a supportive trial for existing data with longer endpoints. “Progression-free survival is probably a better endpoint, but the data for that are immature,” he said. Longer follow-up is needed to show progressionfree survival differences between the two arms. BRIGHT was conducted from April 2009 to June 27, 2012, and randomly assigned 447 patients in a 1:1 ratio to the two treatment arms (224 to BR; 223 to R-CHOP or R-CVP). Investigators could choose either RCHOP or R-CVP at their discretion, prior to the randomization. Patients received up to six cycles during the randomized phase and could receive another two cycles at the investigator’s actions, dizziness and confusional state, neuropathy, and risk of second primary malignancies. Cases of acute myelogenous leukemia have been reported in patients receiving pomalidomide as investigational therapy outside the setting of multiple myeloma. n References 1. U.S. Food and Drug Administration: Pomalidomide. Available at http://www. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm339286.htm. Accessed February 20, 2013. 2. POMALYST® (pomalidomide) capsules prescribing information, Celgene Corporation, February 2013. Available

discretion. Follow-up was 5 years. Demographic and disease characteristics were comparable between the two treatment arms. Mean age was about 60 years, 64% had an ECOG performance status of 0, and about 69% had stage IV disease.

Evaluable Patients Among 213 evaluable patients on BR and 206 on R-CHOP or R-CVP, complete response rates were 31% and 25%, respectively. The complete response ratio of 1.26 met the definition of noninferiority, Dr. Flinn said, “but was not statistically significant for superiority.” Overall response rates were 97% for BR vs 91% for R-CHOP/R-CVP. Toxicity profiles of the two arms were different. Adverse events of all grades included a higher incidence of nausea/vomiting, pyrexia, chills, drug hypersensitivity reactions, decreased appetite, rash, and pruritus for the BR arm, and a higher incidence of constipation, paresthesia, peripheral neuropathy, and alopecia for R-CHOP/RCVP arms. Grade 3 or higher adverse events that were increased in the BR arm included hypersensitivity reactions, opportunistic infection, and respiratory/thoracic disorders. More frequent febrile neutropenia, alopecia, and neuropathy were seen in the chemotherapy arms. Despite the continued on page 32

at http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204026lbl.pdf. Accessed February 20, 2013.

REPORT ADVERSE EVENTS Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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Bendamustine/Rituximab continued from page 31

use of growth factor support, patients treated with R-CHOP had a higher incidence of grade 3 or more hematologic adverse events including neutropenia and lymphopenia.

John M. Burke, MD

More deaths occurred in the BR group (six patients, due to pneumonia, respiratory failure, and sepsis; acute respiratory failure; cardiac arrest; pneumonia; chronic obstructive pulmonary disease; lung cancer) than in the R-CHOP/R-CVP group (one patient, due to sepsis). “There was a much greater use of growth factors in the R-CHOP arm, so lack of growth factor support could not explain the increased neutropenia observed with R-CHOP,” Dr. Flinn said.

Quality-of-life Study A substudy of BRIGHT compared quality of life in both arms of the trial,

based on patient-reported responses to 30 questions pertaining to symptoms and quality of life.4 Patients were surveyed at baseline and during intervals throughout treatment up to cycle 6. Higher scores on functional scales and global health measures equaled better outcome, while higher scores on symptom scales reflected greater severity of symptoms. “In this study, patients treated with BR had improved global health status, physical function, social and emotional function, fatigue, dyspnea, and constipation compared with the RCHOP arm,” stated lead author John M. Burke, MD, a clinician at Rocky Mountain Cancer Centers, Aurora, Colorado. n

Disclosure: Dr. Flinn reported no potential conflicts of interest. Dr. Burke has served on advisory boards for Alexion, Dendreon, Genomic Health, Seattle Genetics, and Spectrum.

References 1. Flinn I, Van der Jagt R, Kahl B, et al: An open-label, randomized stdy of bendamustine and rituximab compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line treatment of advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma: The Bright study. 2012 ASH Annual Meeting. Abstract 902. Presented December 11, 2012.

EXPERT POINT OF VIEW

“T

he BRIGHT study had a noninferiority design, but I question why BR was not found superior, because the StiL trial showed a huge difference in progression-free survival favoring BR,” said Martin Dreyling, MD, Professor at the University of Munich in Germany. “In BRIGHT, BR achieved higher remission rates than R-CVP (95% vs 83%) but was comparable to R-CHOP (93% vs 90%) in indolent lymphoma, which may be more meaningful than the total Martin Dreyling, MD numbers for a mixed patient population. Also, the toxicity in BRIGHT was similar between the two arms. My reading is that BR should be less toxic,” he added. “To put BR in perspective, it is better tolerated and noninferior to RCHOP. BR is a good alternative to R-CHOP for elderly patients and other patients with poor performance status. To those who claim that BR is the new standard of care, I would say, ‘BR is one of the standards of care for indolent NHL and MCL,’” Dr. Dreyling commented. n Disclosure: Dr. Dreyling receives support for clinical trials from Mundipharma.

2. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab (BR) versus CHOP plus rituximab (CHOPR) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1study. 2012 ASCO Annual Meeting. Abstract 3. Presented June 3, 2012. 3. Knauf W, Abenhardt, Nusch A, et al: Bendamustine-rituximab replaces RCHOP as “standard of care” in the treatment of indolent non-Hodgkin lymphoma

in German hematology outpatient centres. 2012 ASH Annual Meeting. Abstract 3666. Presented December 10, 2012. 4. Burke J, Van der Jagt R, Kahl B, et al: Differences in quality of life between bendamustine plus rituximab compared with standard first-line treatments in patients with previously untreated advanced indolent non-Hodgkin’s lymphoma or mantle cell lymphoma. 2012 ASH Annual Meeting. Abstract 155. Presented December 9, 2012.

IMPORTANT VIDEO HIGHLIGHTS FROM

ASH 2012

Dr. James Armitage, Editor-in-chief of The ASCO Post, interviews leading experts:

Dr. Richard Fisher on lymphomas

Dr. Hagop Kantarjian on leukemias

Dr. Sagar Lonial on multiple myelomas

Presented by The ASCO Post. Recorded at ASH 2012 in Atlanta, Georgia. Visit ASCOPost.com to view webcast program.

ASCOPost.com | MARCH 15, 2013

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News Hematology

Quizartinib Data Encouraging in Phase II Investigations of FLT3 Mutation–positive Acute Myeloid Leukemia By Alice Goodman

he investigational oral FLT3 inhibitor quizartinib appears to be a safe and effective treatment for patients with relapsed or refractory acute myeloid leukemia (AML), according to results of a phase II trial presented at the 54th Annual Meeting of the American Society of Hematology (ASH) in Atlanta.1,2 Quizartinib achieved high response rates in a difficult-to-treat cohort of patients, and some of the responses were durable. Quizartinib treatment enabled more than one-third to go on to stem cell transplant. Phase III studies of this compound are in the planning stages.

Potent and Selective Agent Acute myeloid leukemia is a rapidly proliferating cancer. Internal tandem duplication of the FLT3 gene occurs in up to one-third of patients with AML and is associated with more aggressive disease and failure of standard treatment. Stem cell transplant can be used, but only in patients who achieve remission. Therefore, effective treatments are needed if patients require transplant. “Quizartinib is a potent and selective FLT3 inhibitor, and is the first drug designed as a selective FLT3 in-

failed. Cohort 2 included patients over age 18 who presented with relapsed or refractory AML and had

been given salvage chemotherapy after failure of prior treatment or relapse after a stem cell transplant. The

continued on page 34

INHIBIT ANDROGEN PRODUCTION

Mark J. Levis, MD

hibitor. It is 10 to 50 times more potent in humans than other FLT3 inhibitors that have been studied. We have been trying to attack this enzyme for the last 10 years,” stated lead author Mark J. Levis, MD, Associate Professor at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore. The phase II trial enrolled two cohorts of patients (N = 271). Cohort 1 included patients aged 60 or older with the FLT3 mutation who had a recent first relapse or for whom standard chemotherapy had

majority of patients in both cohorts had the FLT3 mutation.

BLOCK THE ANDROGEN RECEPTOR

Learn more at inhibitandrogen.com/distinct *Other treatment options may also be considered. References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines® ) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN ®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 10/12 08Z12191

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News

Quizartinib in AML

peared to be well tolerated with manageable toxicity, Cohort 2 Results he added. The most comAt the ASH meeting, Dr. Levis remon treatment-emergent ported results in cohort 2 in 137 paadverse events were nausea tients (99 with FLT3 mutations and (53%), vomiting (41%), 38 without).1 Cohort 1 results were febrile neutropenia (38%), presented in a separate session (see diarrhea (37%), anemia below). (34%), QT-interval pro“The FLT3-positive cohort 2 was a (27%), and Jorge Cortes, MD Aaron Schimmer, MD longation rough group, the essential equivalent fatigue (24%). The QTpatients and 25.6 weeks for FLT3 muof being on death row. They were runinterval prolongations were asymptation–negative patients. Quizartinib ning out of options,” Dr. Levis said. tomatic and transient, and there were no grade�� 4 events or deaths associenabled 37% of all patients to go on to Quizartinib was given once daily at ated with this abnormality, Dr. Lestem cell transplant. Among all transa starting dose of 90 mg/d in women vis said. Progressive disease was the planted patients, median overall surand 135 mg/d in men in 28-day cycles most common event leading to treatvival was 33.3 weeks, vs 17.7 weeks for until disease progression or unacceptment discontinuations among the those who did not undergo transplant. able toxicity. In cohort 2, the complete 18% who stopped taking quizartinib. Among the group with FLT3 mutaresponse rate was 46% in 100 patients tion–negative AML who underwent with FLT3 mutation–positive disease Cohort 1 Results stem cell transplant, median overall and 32% in FLT3 mutation–negative Results in the older cohort 1, survival had not yet been reached at patients. presented by Jorge Cortes, MD, the time of the ASH meeting, whereas “Seventy-five percent of cohort 2 Deputy Chair and Professor of Medmedian overall survival was 20.8 weeks had a reasonable, dramatic response— icine in the Department of Leukein those without stem cell transplant. all cleared from the blood and mostly mia, The University of Texas MD “In patients with of FLT3 mutations cleared the marrow,” he said. Anderson Cancer Center, Houston, who were bridged to an allogeneic Survival Data showed that complete responses transplant, the survival is extremely Median overall survival was 22.9 were achieved in more than 50% of encouraging,” Dr. Levis noted. weeks for FLT3 mutation–positive elderly patients with FLT3 mutaIn this small study, quizartinib aption–positive disease.2 These results were considered clinically meaningQuizartinib in Highly Resistant AML ful and allowed some patients to be bridged to stem cell transplant. ■■ A phase II trial of the novel targeted agent quizartinib demonstrated a Slightly less than one-third of FLT3 complete response rate of 46% and manageable toxicity in patients with mutation–negative patients achieved highly resistant FLT3 mutation–positive acute myeloid leukemia. a complete response. The side-effect ■■ Quizartinib enabled more than one-third of patients to go on to stem cell profile of quizartinib was similar to transplant, with promising improvements in survival. that in cohort 2. The investigators continued from page 33

concluded that quizartinib may be an option for elderly AML patients who require further therapy, but additional studies are needed. Commenting on this trial, Aaron Schimmer, MD, Princess Margaret Cancer Center University Health Toronto, Canada, was enthusiastic about these preliminary results with a targeted therapy. “We see that what we have learned about genetic abnormalities in hematologic cancers is paying off in terms of therapy. Quizartinib is a drug that works on patients with a specific mutation who no longer respond to other therapies.” n

Disclosure: Drs. Levis and Schimmer reported no potential conflicts of interest. Dr. Cortes receives research support from Ambit, Astellas, Ariad, Novartis, and Arog, and he is a consultant for Ariad.

References 1. Levis MJ, Perl AE, Dombret H, et al: Final results of a phase 2 open-label monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. 2102 ASH Annual Meeting. Abstract 673. Presented December 10, 2012. 2. Cortes J, Perl AE, Dombret H, et al: Final results of a phase 2 open-label monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years old with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. 2012 Annual Meeting of ASH. Abstract 48. Presented December 9, 2012.

Cytarabine in Conditioning Regimen for Younger Patients with MCL By Alice Goodman

igh-dose cytarabine should be incorporated into the induction regimen of younger patients with mantle cell lymphoma (MCL) before autologous stem cell transplantation, according to final results of the MCL Younger Trial of the European Mantle Cell Lymphoma Network, presented at the ASH Annual Meeting.1 The study demonstrated that three alternating courses of R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, prednisone) and R-DHAP (rituximab plus dexamethasone, cytarabine, cisplatin), compared to RCHOP, increased clinical complete response rate in MCL patients following

Olivier Hermine, MD, PhD

induction as well as molecular response, according to polymerase chain reaction analysis (ie, minimal residual disease). “This regimen also improved time to treatment failure in all risk groups and was related to increased [minimal residual disease]–negative status, which is the best prognosis factor,

and showed a trend toward improved overall survival with a good safety profile,” stated lead author Olivier Hermine, MD, PhD, University of Paris Descartes and Hopital Necker, Paris. “Regimens that include highdose [cytarabine] should become the new gold standard,” he said. The study compared three alternating courses of R-CHOP and R-DHAP followed by a myeloablative regimen

and autologous stem cell transplantation vs six courses of R-CHOP followed by myeloablative radiochemotherapy and autologous stem cell transplantation in younger patients with MCL. The study randomly assigned 497 patients aged 65 or younger with stage II to IV MCL to the two arms. A total of 233 in the RCHOP arm and 232 in the R-CHOP/RDHAP arm were evaluable. continued on page 35

Cytarabine in Mantle Cell Lymphoma ■■ Use of high-dose cytarabine improved the rate of complete response

and the rate of minimal residual disease negativity in patients aged 65 or younger with mantle cell lymphoma.

■■ Minimal residual disease negativity was linked to time to treatment failure. ■■ Safety was acceptable with high-dose cytarabine.

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News

Cytarabine in MCL continued from page 34

At baseline, median age was 55 years, 79% were male, and about 82% had stage IV disease. Approximately 62% were low risk, 24% were intermediate risk, and 14% were high risk. Following induction, responses were significantly better in the cytarabinecontaining arm: The complete response rate was 25% in the R-CHOP arm vs 36% in the R-CHOP/R-DHAP arm =�� .0077); the complete response/un(P �� confirmed complete response rate was 39% vs 55%, respectively (P = .0013). Overall response (complete response, unconfirmed complete response, or partial response) was not significantly different: 90% and 95%, respectively. A similar percentage of patients in both arms underwent autologous stem cell transplantation: 83% vs 80%. Response rate was high in both arms following stem cell transplant: 97% vs 98%.

best survival rates were in the low-risk group of younger MCL patients, with a strong trend in the R-CHOP/R-DHAP arm. Most importantly, at the time of analysis, overall survival in the cytarabine arm was also superior to the control arm (not reached vs 82 months, P = .045). “No matter which conditioning

regimen is used, high-dose [cytarabine] should be used in the induction regimen of younger patients with MCL. This study sets the standard and confirms the addition of [cytarabine] worldwide,” stated Martin Dreyling, MD, University of Munich, Germany. n Disclosure: Drs. Hermine and Dreyling reported no potential conflicts of interest.

Reference 1. Hermine O, et al: Alternating courses of 3x CHOP and 3x DHAP + rituximab followed by a high dose Ara-C containing myeloablative regimen and ASCT increases overall survival when compared to 6 courses of CHOP + rituximab followed by radioimmunotherapy and ASCT in mantle cell lymphoma. 2012 ASH Annual Meeting. Abstract 151. Presented December 9, 2012.

Key Findings At a median follow-up of 53 months, time to treatment failure was a median of 46 months in the R-CHOP arm vs 88 months in the R-CHOP/R-DHAP arm (P = .0382). Patients in the R-CHOP arm had almost twice the number of events related to treatment failure: 122 vs 69. The relapse rate following complete response/unconfirmed complete response/partial response was twice as high in the R-CHOP arm: 88 vs 44, respectively. Significant differences in time to treatment failure favoring the RDHAP/R-CHOP arm were present in =�� .0004) and intermedithe low-risk (P �� ate-risk (P = .053) groups. The investigators found that achievement of minimal residual disease postinduction was the strongest independent prognostic factor of outcome (P = .001), even stronger than Mantle Cell Lymphoma International Prognostic Index (MIPI) risk status (P = .008), treatment arm, or complete response. In pooled trials of the European Mantle Cell Lymphoma Network, minimal residual disease was significantly associated with longer duration of remission. Compared with R-CHOP, RCHOP/R-DHAP was associated with higher rates of grade 3 or 4 myelosuppression and similar rates of other grade 3 and 4 toxicities during induction. During autologous stem cell transplantation, both treatment arms had similar rates of grade 3 and 4 toxicities. At the time of the ASH meeting, median survival had not yet been reached in either arm. The

Androgen levels may impact antiandrogen therapy.1-3 Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed. Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

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JCO Spotlight Thoracic Oncology

Patients Receiving Palliative Radiation Therapy for Metastatic Non–Small Cell Lung Cancer May Be Overtreated By Matthew Stenger

any patients receiving palliative radiation therapy to the bone or chest for metastatic non– small cell lung cancer (NSCLC) may be receiving a greater number of treatments and higher doses than are supported by current evidence, according to a Cancer Care and Outcomes Research and Surveillance Consortium (CanCORS) study reported in the Journal of Clinical Oncology by Aileen B. Chen, MD,

MPP, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, and colleagues.1 As reviewed by the authors, available evidence indicates that singlefraction radiotherapy for uncomplicated bone metastases is effective in most patients; no difference in pain relief has been observed between single-fraction (5–15 Gy total dose) and multifraction (1530 Gy in 3–10 fractions) radiotherapy, although re-

Value-based Effective Care By Lynn D. Wilson, MD, MPH, FASTRO

he study by Chen and colleagues addresses the extremely important topic of the use and delivery schedule for radiotherapy in palliation for patients with metastatic lung cancer. The number of patients who will be considered candidates for such therapy in the United States and around the world each year is substantial. The study reveals that practice is often not consistent with what is supported by level 1 evidence, and suggests that clinicians’ decisions could be influenced by financial implications. Lynn D. Wilson, MD, MPH, FASTRO Only 6% of patients who received radiotherapy for palliation of bone metastasis were treated with a single fraction.

Further Considerations Obviously, each patient has individualized care needs, and multiple factors must be taken into account when deciding upon the most appropriate therapeutic regimen. Cancer treatment certainly never can be encapsulated into a “one size fits all” approach, despite what the best evidence may suggest. Patient convenience, best clinical practice (based on evidence if it’s available), and provision of value-based, effective care are concepts that need to be at the forefront of clinical management. Cost is important, and we should decrease cost when it can be done in a way that is of no detriment to the patient. Cost comes in many forms, including system finances, patient inconvenience, patient discomfort, patient/family stress, and quality of life. The biggest cost to the patient, who may only have weeks or a few months to live, may be in the time spent traveling back and forth for multiple treatments that may not have any significantly better chance of improving palliation in comparison to a single visit. We all need to think more about these issues when we are asked to help a patient in need of palliative care. We have excellent evidence to help guide our decisions in palliation of metastatic disease to the bone. We need to consider each patient individually, while we also should always try to apply the best available evidence aggressively in actual clinical practice. We should make decisions that are best for the patient and economically responsible to the entire health-care system. It’s time for a change. n Disclosure: Dr. Wilson receives clinical research support from Merck.

Dr. Wilson is Professor, Vice Chairman and Clinical Director, and Residency Training Program Director, Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.

treatment has been more common in patients receiving single-fraction radiotherapy. Most data indicate that shorter, lower-dose radiotherapy to the chest (eg, 10–35 Gy in 1–10 daily or 16 twice-daily fractions) produces palliation of symptoms equivalent to higher-dose treatment with less treatment-related adverse effects. Though analyses also suggest a potential small short-term survival advantage for modestly higher palliative doses (over about 30 Gy in 10 fractions), significantly higher doses have not been adequately tested.

all patients, 51% received at least one course of chemotherapy after diagnosis, 6% had surgery for the primary tumor, and 6% had surgery for a metastatic site.

Factors Associated with Radiotherapy On multivariate analysis, there were no significant associations of receipt of radiotherapy with sex, marital status, race, comorbidity, or

Study Details The CanCORS study analyzed palliative radiotherapy use in 1,574 patients diagnosed with metastatic NSCLC between 2003 and 2005; patients were from participating CanCORS sites in Northern California, Los Angeles County, North Carolina, Iowa, or Alabama or were receiving care in any of 10 Veterans Administration sites or 5 large health maintenance organizations. The median age of the cohort was 68 years, and 65% were male. Median survival following metastatic diagnosis was 4.7 months, with 20% of patients remaining alive at 15 months, the end of the observation period. Overall, 895 patients (57%) had at least one visit with a radiation oncologist after diagnosis of metastatic disease, with 780 patients (87% of those with visits and 50% of the total cohort) receiving at least one course of radiotherapy. Among those receiving radiotherapy, 22% received radiation to the brain, 21% to the chest, and 12% to the bone. Among

Aileen B. Chen, MD, MPP

insurance type. Patients receiving systemic chemotherapy (56% vs 42% of those not receiving chemotherapy, odds ratio [OR] = 1.66, P < .001) and those who had surgery for a metastatic site (65% vs 49% of those not receiving such surgery, OR = 1.90, P = .006) were more likely to receive radiotherapy. Older patients (39% of patients aged > 80 years vs 61% of patients aged < 55 years, OR = 0.47, =�� .003) and those receiving surP �� gery for the primary site (36% vs 50% of those not receiving such surgery, OR = 0.41, P < .001) were less likely to receive radiotherapy.

Fraction and Dose Findings Among 194 patients receiving palliative radiotherapy to the bone

Palliative Radiotherapy in NSCLC ■■ Whereas current evidence suggests that single-fraction radiation therapy is

effective for palliative treatment in most patients with uncomplicated bone metastases from non–small cell lung cancer (NSCLC), the CanCORS study showed that only 6% of patients received single-fraction radiotherapy.

■■ Although there may be a short-term survival benefit for patients receiving modestly high doses of palliative radiation to the chest, the CanCORS study showed that 42% of patients received more than 20 fractions and 33% received more than 50 Gy, which exceeds the intensity of palliative radiation tested or supported by current evidence.

■■ Patients treated in integrated networks received fewer fractions and lower total doses, which falls more closely in line with current evidence.

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JCO Spotlight

with a known number of fractions, 50% received 6 to 10 treatments, 20% received 5 or fewer, and 6% received a single fraction. Among 206 patients receiving a known dose, 49% received between 21 and 30 Gy. Among 297 patients receiving palliative radiotherapy to the chest with a known number of fractions, 42% received more than 20 fractions. Among 319 with a known dose, 65% received more than 30 Gy and 33% received more than 50 Gy. Several factors were associated with number of fractions and dose on multivariate analysis. Patients treated within integrated networks (ie, staff model HMOs or the Veterans Administration network) received an average of 3.4 fewer fractions (P = .001) and a dose 4.0 Gy lower (P = .049) to the bone than

bone or chest receive higher doses and more fractions than clinical trial data supports.” They continued, “Our observation that patients treated in integrated networks receive lower total doses and fewer fractions suggests that provider characteristics, organizational structures and processes,

and/or financial incentives may influence clinical practice. However, further study is necessary to clarify the reasons for the extent of overly intensive care and to develop strategies for bringing evidence and practice into better alignment.” n Disclosure: Dr. Jennifer Malin has been compensated for employment or a leadership

position at WellPoint. All other authors of the study reported no potential conflicts of interest.

Reference 1. Chen AB, Cronin A, Weeks JC, et al: Palliative radiation therapy practice in patients with metastatic non-smallcell lung cancer. J Clin Oncol. January 7, 2013 (early release online).

Further study is necessary to clarify the reasons for the extent of overly intensive care and to develop strategies for bringing evidence and practice into better alignment. those not in an integrated network; these patients also received 2.9 fewer fractions (P = .047) and a dose 4.8 Gy lower (P = .04) to the chest. Patients with greater comorbidity scores tended to receive higher doses to the bone (overall P = .005) with no difference in number of fractions. Patients receiving chemotherapy after diagnosis received 7.0 more fractions and a dose 11.3 Gy higher <�� .001) than pato the chest (both P �� tients not receiving chemotherapy.

Conclusions The authors concluded, “Palliative [radiotherapy] is frequently used in patients with metastatic NSCLC and has clearly demonstrated ability to improve quality of life in those patients. However, treatment can incur significant time and monetary costs for patients with limited life expectancy. We found that a substantial proportion of patients treated to the

Learn more at inhibitandrogen.com/sequence *Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel. mCRPC=metastatic castration-resistant prostate cancer. References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

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JCO Spotlight Thoracic Oncology

No Benefit of Adding Carboplatin to Pemetrexed in Second-line Treatment of Patients With Advanced Non–Small Cell Lung Cancer By Matthew Stenger

n Italian randomized phase II study (GOIRC 02-2006 study) recently reported in Journal of Clinical Oncology by Andrea Ardizzoni, MD, of Azienda Ospedaliero-Universitaria in Parma, Italy, and colleagues showed no progression-free survival benefit of adding carboplatin to pemetrexed (Alimta) in second-line treatment of advanced non–small cell lung cancer (NSCLC).

Study Design In GOIRC 02-2006, 239 patients with advanced NSCLC who had disease progression during or after firstline platinum-based chemotherapy were randomly assigned to receive pemetrexed plus carboplatin (n = 119) or pemetrexed alone (n�� = 120). Pemetrexed was given at 500 mg/m2 and carboplatin at area under the curve of 5 on day 1 of a 21-day cycle. Patients in both the pemetrexedplus-carboplatin and pemetrexed-alone groups had a median age of 64 years, 76% and 72% were male, 63% and 58% had ECOG performance status of 0, 82% and 83% had stage IV disease, 72% and 71% had adenocarcinoma, 37.5% and 35% had objective response to firstline platinum-based chemotherapy, and 62.5% and 64% had a treatment-free interval of at least 3 months. The primary endpoint was progression-free survival. A preplanned pooled analysis of the results of this study combined with those of a nearly identical Dutch phase II study (NVALT7) was performed to assess the effect of the addition of carboplatin to pemetrexed on overall survival.

Key Results Both groups had a median of four treatment cycles, and the median follow up was 22.2 months. Median progression-free survival was 3.5 months in the carboplatin-plus-pemetrexed group vs 3.6 months in the pemetrexed group (hazard ratio [HR] = 1.05, P = .706). Response occurred in 12.6% vs 12.5% of patients (P = .980). Median overall survival was 9.2 vs 8.8 months (HR = 0.97, P = .834). Grade 3 or 4 hematologic toxicities and the most clinically relevant nonhematologic adverse events were infrecontinued on page 55

EXPERT POINT OF VIEW

n an accompanying editorial, Nasser H. Hanna, MD, of Indiana University, Indianapolis, suggested that although the question of two chemotherapy drugs vs one in this setting made sense at the time GOIRC 02-2006 was initiated, advances in understanding of the heterogeneity of non–small cell lung cancer (NSCLC) and in targeted therapies have reduced the value of these types of comparisons in advancing therapeutics. Dr. Hanna noted that a recent meta-analysis of two drugs vs one drug in second-line treatment of advanced NSCLC indicated that response rates and progressionfree survival were improved with a twodrug approach, but overall survival was not improved and toxicity was increased with combination treatment.1

Are We Asking the Right Questions? “Do we need additional studies of this nature?” Dr. Hanna asked. “In a time of substantial scientific advances, are we still asking the right questions? At the time the trial by Ardizzoni et al was conceived, my answer would have been yes. In 2012, the answer is no.” He continued, “Our understanding of lung cancer has markedly advanced since the conception of [this] trial. Lung cancer is no longer only thought of as small-cell lung cancer, in which chemotherapy and radiation have substantial benefits, albeit shortlived in most patients, and NSCLC, in which chemotherapy and radiation have modest benefits. We must now think of NSCLC as nonsquamous non–small cell or squamous cell lung cancer. We must consider several issues including whether patients are bevacizumab [Avastin] eligible, their smoking history, and the presence of molecular abnormalities such as EGFR mutation, ALK gene rearrangement, ROS-1 gene rearrangement, or KRAS mutation. Should we give patients maintenance therapy, and if so, will it be switch maintenance, whereby we change to a different drug before disease progression in patients receiving first-line therapy, or continuation maintenance, whereby we

continue one or more drugs given in the first-line therapy until disease progression or intolerable adverse effects? These are the key clinical questions that must be addressed for patients with advanced NSCLC.”

Further Considerations Each of these questions continues to have an impact on development of approaches to treatment-naive patients with advanced lung cancer. Additional factors that need to be considered for

mous cell disease, the outcome should be considered as providing a rationale for using carboplatin alone in this setting. He stated, “Because of the spoils of testable hypotheses today, it is doubtful that this question will or should be answered in a separate clinical trial.”

Conclusions Dr. Hanna concluded, “The understanding of the molecular underpinnings of NSCLC has brought hope and more successful treatment, including

Our understanding of lung cancer has markedly advanced since the conception of [this] trial. —Nasser H. Hanna, MD

second-line treatment include whether molecular status at diagnosis affects choices of second-line treatment or even reflects status of disease at progression and whether patients should undergo repeat biopsy at progression. As stated by Dr. Hanna, given the array of new targets and targeted agents, researchers are now designing trials that ask which drugs should be used for which patients, rather than simply whether one vs two drugs should be used or how much of each drug should be used. He cites as an example in this regard a report from an MD Anderson Cancer Center Initiative for personalized medicine in which patients with identified molecular targets were matched with phase I trials of targetspecific drugs; response rates were 27% in target-matched patients and 5% in empirically treated patients.2 With regard to the pooled analysis finding of overall and progressionfree survival benefit with combination treatment in patients with squamous cell cancer, Dr. Hanna asked whether, given that pemetrexed (Alimta) is believed to have minimal activity in squa-

the discovery of epidermal growth factor receptor tyrosine kinase inhibitors for patients with EGFR mutations and anaplastic lymphoma kinase inhibitors for patients with ALK gene rearrangements. For these patients, gains in survival are not measured in weeks or months but, in some cases, years. History teaches us that substantial gains in the treatment of NSCLC will not come from minor manipulations in dose, schedule, and sequencing of these newer agents, just as it has not for classic chemotherapy drugs. As the saying goes, those that do not know their history are destined to repeat it.” n Disclosure: Dr. Hanna has received research funding from AstraZeneca and Eli Lilly.

References 1. Hanna NH: Two drugs versus one drug in non–small-cell lung cancer: Are we asking the right questions (editorial)? J Clin Oncol 30:4454-4455, 2012. 2. Tsimberidou AM, Iskander NG, Hong DS, et al: Personalized medicine in a phase I clinical trials program: The M.D. Anderson Cancer Center Initiative. 2011 ASCO Annual Meeting. Abstract CRA2500. Presented June 3, 2011.

Because Endocrine Monotherapy Can Only Take You So Far

In postmenopausal women with advanced HR+, HER2-negative breast cancer after failure of treatment with letrozole or anastrozole

Change the Treatment Paradigm With AFINITOR Plus Exemestane AFINITOR plus exemestane more than doubles median progression-free survival (PFS) over exemestane monotherapy1

Median PFS in BOLERO-2 (Investigator Radiological Review)1 100

HR=0.45 [95% CI, 0.38-0.54] Log-rank P value: <0.0001

7.8 months Placebo plus exemestane: 3.2 months

AFINITOR plus exemestane:

PFS Probability (%)

Median PFS: 3.2 months

55%

Median PFS: 7.8 months

reduction in risk of progression or death2

20 AFINITOR plus exemestane (n/N=310/485) Placebo plus exemestane (n/N=200/239)

0 0

Time (months)

• Median PFS was 7.8 months with AFINITOR® (everolimus) Tablets plus exemestane [95% CI, 6.9-8.5] vs 3.2 months with placebo plus exemestane

[95% CI, 2.8-4.1] (P<0.0001)1

PFS curves for the 2 treatment arms began to diverge at 6 weeks (the first tumor assessment)1,2 An independent central review confirmed a significant PFS improvement with AFINITOR plus exemestane treatment vs placebo plus exemestane1,2 • Median PFS was 11.0 months with AFINITOR plus exemestane [95% CI, 9.7-15.0] vs 4.1 months with placebo plus exemestane [95% CI, 2.9-5.6]

(HR=0.38 [95% CI, 0.3-0.5]; P<0.0001)1

BOLERO-2=Breast Cancer Trials of Oral Everolimus; HR=hazard ratio.

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AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information.

• AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients • There have been reports of noninfectious pneumonitis, infections, and renal failure (including acute renal failure) in patients taking AFINITOR, some with

fatal outcomes. In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidences of deaths due to any cause within 28 days of the last AFINITOR dose and adverse reactions leading to permanent treatment discontinuation were greater in patients ≥65 years of age compared with patients <65 years of age

• Oral ulceration is the most frequently occurring adverse event and occurred in 44% to 86% of AFINITOR-treated patients across the clinical trial

experience. Most of these events were grade 1/2. Grade 3/4 stomatitis was reported in 4% to 9% of patients

• Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have

also been reported; monitoring of laboratory tests is recommended

• The use of live vaccines and close contact with those who have received live vaccines should be avoided • AFINITOR can cause fetal harm when administered to a pregnant woman

Please see additional Important Safety Information and Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

References: 1. AFINITOR [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012. 2. Data on file. Study CRAD001Y2301. Novartis Pharmaceuticals Corp; 2012.

• Careful monitoring and appropriate dose adjustments for adverse

Important Safety Information. AFINITOR® (everolimus) Tablets is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: • Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed • If symptoms are moderate, patients should be managed with dose interruption until symptoms improve • The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve • For grade 3 cases, interrupt AFINITOR until resolution to grade ≤1 • AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR • The development of pneumonitis has been reported even at a reduced dose Infections: • AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred • Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal • Physicians and patients should be aware of the increased risk of infection with AFINITOR • Treatment of preexisting invasive fungal infections should be completed prior to starting treatment • Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered • Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment Oral Ulceration: • Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients • In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided • Antifungal agents should not be used unless fungal infection has been diagnosed Renal Failure: • Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR Geriatric Patients: • In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥65 years of age compared to 2% in patients <65 years of age • Adverse reactions leading to permanent discontinuation occurred in 33% of patients ≥65 years of age compared with 17% in patients <65 years of age

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

reactions are recommended Laboratory Tests and Monitoring: • Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported • Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter • When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR Drug-Drug Interactions: • Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) • Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) • Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments Hepatic Impairment: • Exposure of everolimus was increased in patients with hepatic impairment • For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended Vaccinations: • The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR Embryo-Fetal Toxicity: • Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment Adverse Reactions: • The most common adverse reactions (incidence ≥30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%), and decreased appetite (30%) • The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%), and diarrhea (2%) Laboratory Abnormalities: • The most common laboratory abnormalities (incidence ≥50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%) • The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%)

Please see Brief Summary of Prescribing Information on adjacent pages. To learn more, please visit www.AFINITOR.com.

10/12

AFB-1043056

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009

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Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-9% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring].

Geriatric Patients In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations]. Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 e Median duration of treatment 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration

Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo c

Key observed laboratory abnormalities are presented in Table 3. Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC Laboratory Parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All Grade Grade All Grade Grade grades 3 4 grades 3 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents That May Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.5) in the full prescribing information and Warnings and Precautions]. Agents That May Decrease Everolimus Blood Concentrations CYP3A4 Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.5) in the full prescribing information]. Drugs That May Have Their Plasma Concentrations Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

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A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use a highly effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Pediatric use of AFINITOR Tablets is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume [see Clinical Studies (14.5) in the full prescribing information]. Improvement in diseaserelated symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least one serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar [see Adverse Reactions (6.5) in the full prescribing information]. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA [see Clinical Pharmacology (12.3) in the full prescribing information].The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA [see Dosage and Administration (2.3, 2.4) in the full prescribing information]. Geriatric Use In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age [see Warnings and Precautions]. In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger subjects. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (ChildPugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Distributed by: Novartis Pharma Stein AG Novartis Pharmaceuticals Corporation Stein, Switzerland East Hanover, New Jersey 07936 © Novartis T2012-153 August 2012

The ASCO Post | MARCH 15, 2013

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Direct from ASCO

ASCO International Expands to Improve Cancer Care Worldwide

s a global community of cancer care providers in more than 100 countries around the world, ASCO is uniquely positioned to improve cancer patient outcomes worldwide—an opportunity that it has seized since the organization’s inception through numerous innovative programs. Building upon this foundation, ASCO recently launched ASCO International, an ambitious 4-year expansion of new programs, initiatives, and research opportunities to increase awareness, improve practice, and foster innovation in cancer care regardless of socioeconomic status and geographic boundaries to make cancer care a global health priority. Fueling the flame for the expansion of ASCO’s international impact, Sandra M. Swain, MD, FACP, current ASCO President and Medical Director, Washington Cancer Institute MedStar Washington Hospital Center, has prioritized the goal of “ensuring global health equity” as part of her presidential theme, “Building Bridges to Conquer Cancer.” Noting that cancer survival rates vary significantly among countries with differing financial and infrastructural resources, Dr. Swain says, “Investment in ASCO International will help build bridges between members, organizations, and

countries, regardless of geography. The goal is to provide clinicians around the world with the tools, knowledge, and training they need to achieve better care for their patients with cancer.”

ASCO’s Current International Reach According to David M. Khayat, MD, PhD, of Pitié-Salpêtrière Hospital in Paris, ASCO’s International Affairs Committee Chair, “Although ASCO has a bold vision for improving cancer care worldwide, the organization has already made significant

many international oncologists to travel to the Annual Meeting, ASCO works with its partner societies to bring highlights of the Annual Meeting to those individuals through “Best of ASCO International.” Faculty include a blend of national and international ASCO members who collaborate to provide scientific highlights and place those highlights into the local practice context. In addition, ASCO works with peer oncology societies to hold joint symposia that showcase oncology themes selected to fit regional needs. The International Affairs Committee

Investment in ASCO International will help build bridges between members, organizations, and countries, regardless of geography. —Sandra M. Swain, MD, FACP

strides toward that goal through its educational offerings and grants and awards programs.” These programs span continents, including many lowand middle-income countries. ASCO’s Annual Meeting is a key forum for international bridge building, with more than half of attendees coming from outside the United States. Recognizing that it is impossible for

reviews proposals for joint symposia on a case-by-case basis.

Education Initiatives ASCO’s training courses serve as another vehicle to provide oncology skills and knowledge to health-care professionals worldwide. For example, in partnership with the European Society of Medical Oncology, ASCO developed

ASCO in

Ac t i on Your source for public policy news and information from ASCO Visit our one-stop source for the latest information on: Policy Information – get the latest news on key legislation and priorities such as access to care, clinical trials and drug shortages Advocacy Tools – take action with ASCO’s ACT Network Position Statements – see ASCO’s positions on current issues

Stay informed by visiting http://ascoaction.asco.org Follow @asco on Twitter

the Global Curriculum, an outline of training topics that includes basic scientific principles, the management and treatment of individual cancers, psychosocial aspects of cancer, patient education, bioethics, legal and economic issues, and specific skills, such as anticancer agent administration. Ten countries have adopted the curriculum. In addition, ASCO partners with national and regional oncology societies worldwide to provide multidisciplinary cancer management courses in low- and middle-income countries, where cancer patients are frequently treated by nonspecialists. Since 2004, this training has been conducted in 16 countries, with more than 2,500 participants. Through similar partnerships with oncology societies worldwide, ASCO also offers palliative care courses, using the National Cancer Institute’s Education in Palliative and End-of-Life Care for Oncology curriculum, and advanced cancer courses, which train experienced oncologists in topics ranging from cancer care in the elderly to cancer genetics and cancer prevention.

Mentoring and Knowledge Exchange Programs Meanwhile, ASCO is committed to mentoring future cancer leaders in developing countries and fostering international networks for research collaboration. To that end, the Conquer Cancer Foundation grants the International Development and Education Award (IDEA), which pairs early-career oncologists in low- and middleincome countries with leading ASCO members in the United States or Canada who serve as scientific mentors. The 205 IDEA alumni from more than 40 countries have created joint research projects with their mentors, obtained fellowships and grants, and joined ASCO’s leadership. The Foundation’s Long-term International Fellowship provides early-career oncologists in low- and middle-income countries with the opportunity to deepen the mentor-mentee relationship through a 1-year fellowship at a mentor’s institution. After completion of the fellowship, award recipients return to their home institutions to share the knowledge they gained. ASCO’s International Cancer Corps

ASCOPost.com | MARCH 15, 2013

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Direct from ASCO

also pairs ASCO volunteers with medical centers in low-resource countries through a partnership with Health Volunteers Oversees, a nonprofit organization committed to improving global health through education. During 1- to 4-week onsite visits, volunteers deliver lectures, provide training, and participate in rounds, fostering relationships of ongoing collaboration.

guide the expansion of its international programs. Those areas include providing oncology instruction for non-specialists by integrating training into existing primary care structures in low-resource countries; offering innovation grants that would spur cancer control solutions for developing

members, ASCO International has great potential to further help cancer professionals provide quality care in our global communities and lessen suffering for people with cancer worldwide.” n

countries; linking members around the world in mentor-mentee pairs; and expanding the International Cancer Corps Program, which will include several new sites over 4 years. Commenting these plans, Dr. Khayat says, “Through the continued support and participation of ASCO

Initiatives to Advance Cancer Research

International Initiatives on the Horizon “Despite the active role that ASCO has played in the global oncology community over the years, the looming challenges, particularly in low- and middle-income countries, require an even greater investment of resources to ensure that cancer care is a global health priority,” says Dr. Swain. Currently, experts estimate that a majority of new cases of cancer occur in lowand middle-income countries and that nearly two-thirds of the deaths from cancer occur in these countries. Moreover, if current trends continue, the global cancer burden will double over the next 20 years, with approximately 70% of new cancer cases occurring in low- and middle-income countries. To address this burden, ASCO has identified priority needs that will

For men with metastatic prostate cancer, a major threat lives in their bones.

A SIGNIFICANT THREAT IN mCRPC

90%

Bone metastases are the leading cause of death in patients with mCRPC.1 In a large cohort study of patients with prostate cancer, mortality at year 1 was nearly 5 times higher in the subgroup of patients who had bone metastases.2 At year 5, survival fell from 56% in patients without bone metastases to just 3% in patients with bone metastases.2 Skeletal-related events (SREs) increase mortality associated with bone metastases in mCRPC.2 Bone metastases often lead to pathologic fractures, spinal cord compression, hypercalcemia, and bone marrow insufficiency—events that can cause intense pain from bone deconstruction and nerve compromise.3 Moreover, SREs are a key driver of mortality in prostate cancer.4 Prostate cancer tumor cells are uniquely suited to proliferate within the bone microenvironment.1 As a result, bone represents the earliest and most common site of prostate cancer metastasis.5 In fact, 84% to 92% of patients with mCRPC show evidence of bone metastases.6,7

OF PATIENTS WITH mCRPC SHOW EVIDENCE OF BONE METASTASES6,7

BONE METASTASES SIGNIFICANTLY DECREASE SURVIVAL2 100

Bone metastases No bone metastases

90 80

Survival probability (%)

In addition to its support of international cancer research through mentoring and knowledge exchange programs, ASCO has worked to increase international participation in Foundation research awards. Between 2010 and 2012, the number of Career Development Award and Young Investigator Award applications from international candidates increased 71%. Meanwhile, ASCO’s Journal of Clinical Oncology is read by more than 24,000 subscribers worldwide, facilitating the international dissemination of cancer research. An additional 24,000 receive the international editions available in eleven foreign languages, and special editions in English are available in India, Greece, North Africa, and the Middle East. To help build the research skills of investigators in developing countries, ASCO partners with national and regional oncology societies worldwide to organize clinical trial workshops to disseminate best practices in study design and execution.

56% alive at 5 years

60 50 40 30 20

3% alive at 5 years

10 0

Years after initial prostate cancer diagnosis Adapted from Nørgaard et al.

CONFRONTING THE THREAT Extending survival in mCRPC patients remains a significant challenge. Recognizing the impact of bone metastases on mortality is an important step towards improving treatment of patients with mCRPC.8 mCRPC: metastatic castration-resistant prostate cancer. References: 1. Jin J-K, Dayyani F, Gallick GE. Steps in prostate cancer progression that lead to bone metastasis. Int J Cancer. 2011;128(11):2545-2561. 2. Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-167. 3. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468. 4. DePuy V, Anstrom KJ, Castel LD, Schulman KA, Weinfurt KP, Saad F. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer. Support Care Cancer. 2007;15(7):869-876. 5. Bubendorf L, Schöpfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578-583. 6. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512. 7. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520. 8. Aljumaily R, Mathew P. Optimal management of bone metastases in prostate cancer. Curr Oncol Rep. 2011;13(3):222-230.

Bayer and the Bayer Cross are registered trademarks of Bayer HealthCare Inc.

600-10-0001-12b

January 2013.

Printed in USA.

The ASCO Post | MARCH 15, 2013

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Direct from ASCO

ASCO Congratulates QOPI-Certified Practices

QCP™: Recognizing Excellence The QOPI® Certification Program (QCP™) recognizes medical oncology and hematology/oncology practices that are committed to delivering the highest quality of cancer care. QCP evaluates an individual practice’s performance in areas that affect patient care and safety. The QOPI Certification Program provides a three-year certification for outpatient hematology-oncology practices. QCP validates processes that demonstrate to patients, payers, and the medical community, a practice’s commitment to quality.

Western Region ARIZONA • Arizona Oncology Associates, PC • Palo Verde Hematology Oncology, Ltd. CALIFORNIA • Cancer Care Associates • Diablo Valley Oncology and Hematology Medical Group • Epic Care • Marin Cancer Care, Inc. • Moores UCSD Cancer Center • Pacific Cancer Medical Center • Palo Alto Medical Foundation • Santa Monica Hematology-Oncology Consultants • St Jude Heritage Medical Group/ Virginia K Crosson Cancer Center • The Chao Family Comprehensive Cancer Center Division of Hematology/Oncology COLORADO • Southwest Oncology, P.C. HAWAII

Southern Region FLORIDA • Advanced Medical Specialties • Cancer Care of North Florida, PA • Cancer Specialists of North Florida • Florida Hospital Cancer Institute • Florida Oncology Association • Holy Cross Hospital, Michael and Dianne Bienes Comprehensive Cancer Center • Space Coast Medical Associates, LLP • University of Miami - Sylvester Comprehensive Cancer Center GEORGIA • Atlanta Hematology & Oncology Associates, P.C. • Harbin Clinic, LLC • Longstreet Cancer Center • Medical Oncology Associates of Augusta, PC LOUISIANA • Louisiana Hematology Oncology Associates • Louisiana Oncology Associates - Lafayette NORTH CAROLINA

• Comprehensive Cancer Centers of Nevada - Las Vegas, NV

• Alamance Regional Cancer Center • Cancer Care of Western North Carolina, PA - Asheville • Cancer Centers of North Carolina • Cape Fear Cancer Specialists • Emerywood Hematology Oncology • Gaston Hematology and Oncology Associates • Levine Cancer Institute • Matthews Hematology Oncology Associates • Oncology Specialists of Charlotte • Physicians East, P.A. • Piedmont Hematology and Oncology • Raab Specialty and Oncology Clinic at Carteret General Hospital • Randolph Cancer Center

NEW MEXICO

PUERTO RICO

• Cancer Center at Presbyterian • Hematology Oncology Associates, P.C. • New Mexico Oncology Hematology Associates, Ltd. • UNM Cancer Research and Treatment Center

• Auxilio Breast Cancer Center

• OnCare Hawaii, Inc. IDAHO • Mountain States Tumor Institute MONTANA • Billings Clinic NEVADA

OREGON • Hematology Oncology Associates, P.C. • NCCCP- Providence Cancer Center WASHINGTON • Cancer Institutes of Washington, PLLC dba Washington Hematology-Oncology • Columbia Basin Hematology Oncology • Puget Sound Cancer Centers

SOUTH CAROLINA • Coastal Cancer Center • Palmetto Hematology Oncology • Self Regional Healthcare Cancer Center TENNESSEE • Tennessee Oncology • The Jones Clinic • The West Clinic TEXAS • Oncology Consultants • The Center for Cancer & Blood Disorders

ASCOPost.com | MARCH 15, 2013

PAGE 49

Direct from ASCO Midwestern Region

Eastern Region

ILLINOIS

CONNECTICUT

• Affiliated Oncologists, LLC • Cancer Care Specialists of Central Illinois, SC • Center for Cancer Care at OSF Saint Anthony Medical Center • Community General Hospital Medical Center • Creticos Cancer Center Advocate Illinois Masonic Medical Center • Division of Hematology/Oncology-Northwestern University Feinberg School of Medicine • Dreyer Cancer Center • Edward Hematology Oncology Group • Hematology Oncology Consultants, Ltd. • Illinois Cancer Specialists • Illinois CancerCare, P.C. • Joliet Oncology-Hematology Associates, Ltd. • North Shore Oncology-Hematology Associates, Ltd. • NorthShore University HealthSystem Medical Group Kellogg Cancer Centers • Northwest Oncology and Hematology, S.C. • Oncology Hematology Associates of Northern Illinois, Ltd. • Oncology Specialists, S.C. • Springfield Clinic Oncology

• Connecticut Multispecialty Group - Division of Hematology, Oncology • Norwalk Medical Group, P.C. • Western Connecticut Medical Group P.C.; Department of Medical Oncology and Hematology

INDIANA

MASSACHUSETTS

• IU Simon Cancer Center Hematology Oncology • Michiana Hematology-Oncology, P.C. IOWA • Medical Associates Clinic Oncology • Medical Oncology and Hematology Associates • Oncology Associates at Mercy Cedar Rapids • Iowa Blood & Cancer Care of Physicians' Clinic of Iowa KANSAS • Kansas City Cancer Center • The University of Kansas Cancer Center KENTUCKY • Charach Cancer Treatment Center • CBC Group Consulting in Blood Disorders & Cancer • Louisville Oncology MICHIGAN • Marquette General Hematology/Oncology • Northern Michigan Hematology/Oncology • Southwest Michigan Oncology Associates, PLLC • Sparrow Regional Cancer Ctr. - Sparrow Medical Oncology • University of Michigan Cancer Center • West Michigan Cancer Center MINNESOTA • HCMC Comprehensive Cancer Center • Park Nicollet Frauenshuh Cancer Center MISSOURI • Truman Medical Center NEBRASKA • Nebraska Hematology Oncology PC • St. Francis Cancer Treatment Center

DELAWARE • Beebe Medical Center/Tunnell Cancer Center • Medical Oncology Hematology Consultants, PA • Regional Hematology and Oncology, P.A. MAINE • CancerCare of Maine - Lafayette Family Cancer Center • CMMG Hematology Oncology Associates • MaineGeneral Medical Center Harold Alfond Center for Cancer Care MARYLAND • Annapolis Oncology Center • Carolyn B. Hendricks, MD, PA • Oncology Hematology Associates - Weinberg Cancer Institute • Saint Agnes Hospital

• Baystate Regional Cancer Program • Beth Israel Deaconess Medical Center Cancer Center • Commonwealth Hematology Oncology • Dana-Farber/Brigham and Women's Cancer Center at Milford Regional Medical Center • Hematology Oncology Specialists of Cape Cod • Mass General / North Shore Cancer Center • New England Hematology Oncology Associates • Southcoast Centers for Cancer Care NEW HAMPSHIRE • New Hampshire Hematology-Oncology NEW JERSEY • Saint Barnabas Cancer Center NEW YORK • Buffalo Medical Group, PC • Crystal Run Healthcare, LLP • Hematology Oncology Associates of Brooklyn • Hematology Oncology Associates of Central New York • James P. Wilmot Cancer Center/URMC • Maimonides Cancer Center • Pluta Cancer Center • Roswell Park Cancer Institute • WestMed Medical Group • Winthrop Oncology and Hematology Associates, P.C. PENNSYLVANIA • Berks Hematology Oncology Associates • Consultants in Medical Oncology and Hematology, PC • Geisinger Clinic • Hematology & Oncology Associates of Northeastern PA, PC • Hematology Oncology Associates, Allentown • UPMC Cancer Center • Vita Medical Associates, P.C., Bethlehem

NORTH DAKOTA

RHODE ISLAND

• Roger Maris Cancer Center

• Adele R. Decof Comprehensive Cancer Center • Rhode Island Hospital, The Comprehensive Cancer Center • Roger Williams Medical Center • The Cancer Center at Memorial Hospital of Rhode Island

OHIO • Genesis Hematology and Cancer Treatment Center • HOA Cancer Center Promedica Hematology Oncology • Lake Health/University Hospitals Seidman Cancer Center • Ohio Cancer Specialists Inc. • Oncology Hematology Care, Inc. • Summit Oncology Associates, Inc. - Akron • Toledo Clinic Cancer Centers SOUTH DAKOTA • Sanford Hematology & Oncology WISCONSIN • Fox Valley Hematology & Oncology, SC • Gundersen Lutheran Center for Cancer and Blood Disorders • Mayo Clinic Health System, Franciscan Healthcare

VIRGINIA • Virginia Cancer Specialists • Blue Ridge Cancer Care • Hahn Cancer Center - Hematology Oncology Associates • Lynchburg Hematology Oncology • Peninsula Cancer Institute/Cancer Specialists of Tidewater • Virginia Cancer Institute WASHINGTON, D.C. • Washington Cancer Institute WEST VIRGINIA • David Lee Cancer Center

QOPI-certified practices as of January 22, 2013 The practices listed herein currently hold QOPI® Certification and have given their permission to be identified as a QOPI® Certified practice. This list is provided for informational purposes and is not an endorsement or a warranty by the QOPI® Certification Program or ASCO of any specific practice or the care provided by any practice or the practice’s doctors.

The ASCO Post | MARCH 15, 2013

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Direct from ASCO

Journal of Oncology Practice Accepted by MEDLINE® for Indexing

he Journal of Oncology Practice (JOP), published by the American Society of Clinical Oncology (ASCO), has recently been accepted for inclusion in MEDLINE®, the premier bibliographic database of the U.S. National Library of Medicine (NLM). Journals accepted to MEDLINE undergo a rigorous review process and approximately 20% to 25% of journals that apply for indexing on MEDLINE are accepted. Scientific merit is the primary consideration in selecting journals for indexing, including such factors as validity, importance, originality, and contribution to the field. Journals accepted to MEDLINE must also demonstrate a high level of objectiv-

ity, credibility, and quality related to their peer review process and ethical guidelines.

An Invaluable Database “The Journal of Oncology Practice is honored to be among the stellar journals accepted into MEDLINE,” said John V. Cox, DO, Editor-inChief of JOP. “JOP’s acceptance into MEDLINE extends access to important practice research, trends, and care information to oncologists across the country. This honor further establishes JOP as a journal of growing prominence in oncology and is a reflection of its high-quality content.” Articles from MEDLINE indexed journals are more likely to be discovered, cited, and referenced by academicians around the world. Currently, MEDLINE is the source for citations from approximately 5,600 world-

Safe Storage of Cancer Medications

wide journals in 39 languages. The bimonthly Journal of Oncology Practice publishes peerreviewed original research and perspectives on a variety of issues related to health-care delivery, business research, clinical research practices, quality of care initiatives, and health policy. It provides oncologists and other oncology professionals with information to enhance practice efficiency and promote a high standard for quality of patient care. Users may access MEDLINE and search JOP articles, including archived content, at http://www.ncbi. nlm.nih.gov/pubmed. JOP manuscript submissions in any category are welcome and can be submitted at http://jop.msubmit.net. n

ancer.Net provides several new resources to help patients and their caregivers learn about the importance of safe storage, handling, and disposal of cancer medications, particularly those prescribed to relieve pain. These materials include a special article and related podcast available at www.cancer.net/ safestorage, as well as an ASCO Answers fact sheet available to order at www.cancer.net/estore. n

Connecting to Conquer Cancer

ne of the strengths of the Conquer Cancer Foundation of the American Society of Clinical Oncology is our relationships with others who want to join us in creating a world free from the fear of cancer. Our ability to do meaningful work is made possible by the individuals and organizations that support us and share our vision. There are many ways you can connect with the Foundation. ■■ Visit us on the web to learn more about our mission and the programs we support. ■■ Follow us on Twitter for the latest news and events. ■■ Like us on Facebook to show your friends and family that you are working to conquer cancer.

■■ Subscribe to our YouTube channel and learn more about the studies Foundationfunded researchers are conducting. You can also support our mission to fund breakthrough research, share knowledge with physicians and patients worldwide, and support initiatives to ensure that all people have access to high-quality cancer care, by making a donation at www.conquercancerfoundation/ donate. n

Visit the

CONQUER CANCER FOUNDATION on the Web

Website

www.conquercancerfoundation.org

Twitter

@iConquerCancer

Facebook

facebook.com/ConquerCancerFoundation

YouTube

youtube.com/conquercancerfdtn

In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?

Jakafi® (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. June 2012. 2. Verstovsek S, Mesa RA, Gotlib J, et al. N Engl J Med. 2012;366:799-807.

Please see Brief Summary of Full Prescribing Information on the following page.

JAK targeted to make a difference

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2012 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: June 2012 RUX-1040a

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News

Greater Representation of Older Patients in Phase III Trials Needed

he median age of patients diagnosed with advanced non–small cell lung cancer (NSCLC) has steadily increased in recent years and is presently 70 years. Despite this, the elderly are significantly underrepresented in clinical trials. A recent study published in the March 2013 issue of the International Association for the Study of Lung Cancer’s (IASLC) Journal of Thoracic Oncology,1 investigated the degree to which exclusion or underrepresentation of elderly occurs in practice-changing clinical trials in advanced NSCLC. Lead author Adrian G. Sacher, MD, of Princess Margaret Hospital & University Health Network, University of

Toronto, Canada, and colleagues concluded that greater representation of elderly patients in phase III trials is re-

quired to better define evidence-based paradigms in the increasingly elderly NSCLC population. Researchers did an extensive literature search, included articles for review if they were phase III, involved sys-

were identified and their full text reviewed by the authors. Among the 100 most cited trials, 33% excluded elderly patients in their trial design. The average reported median patient age in those trials was

Non–Small Cell Lung Cancer

vs 3.4%), and diarrhea, vomiting, and oral mucositis (each 0.9% vs 1.7%).

cluded a greater proportion of men, better performance status, lower response rate to first-line chemotherapy, shorter treatment-free intervals prior to study treatment, and a greater proportion of patients with adenocarcinoma in GOIRC02-2006. The pooled analysis of overall survival showed no significant difference between carboplatin plus pemetrexed and pemetrexed alone (median 8.7 vs 8.2 months, HR = 0.90, P = .316). A subgroup analysis in the pooled population indicated that the addition of carboplatin to pemetrexed resulted in a significant prolongation of median progression-free survival (3.2 vs 2.0 months, adjusted HR = 0.42, P < .001 for interaction by histologic subtype) and median overall survival (8.7 vs 5.4 months, HR = 0.58, P = .039 for interaction) among patients with squamous tumors. No such dif-

continued from page 38

quent and of similar incidence in the carboplatin-plus-pemetrexed group and the pemetrexed-alone group, including neutropenia (11.6% vs 10.3%), leukopenia (8.0% vs 13.7%), thrombocytopenia (8.0% vs 6.0%), anemia (5.4% vs 8.6%), fatigue (5.4% vs 6.8%), febrile neutropenia (2.7%

temic therapy alone, studied advanced NSCLC, and were conducted between 1980 and 2010. A total of 248 studies

“The study clearly demonstrated that a significant proportion of highly cited phase III clinical trials in advanced NSCLC overtly exclude elderly patients. —Adrian G. Sacher, MD

Overall Survival The NVALT7 study (N = 240) showed a significant prolongation of progression-free survival with the addition of carboplatin to pemetrexed.2 Differences between GOIRC 02-2006 and NVALT7 in-

Carboplatin/Pemetrexed in NSCLC ■■ A phase II study showed no benefit of adding carboplatin to pemetrexed in second-line treatment of advanced non–small cell lung cancer.

■■ The pooled analysis of two phase II studies showed no overall survival

benefit with combination treatment when the entire populations were considered, but did demonstrate progression-free and overall survival benefits in the subgroup of patients with squamous tumors.

■■ A commentary suggested that we have entered an era in which

comparisons of two vs one chemotherapy drugs do little to advance therapeutics in NSCLC.

60.9 years. The authors noted that their investigation “clearly demonstrated that a significant proportion of highly cited phase III clinical trials in advanced NSCLC overtly exclude elderly patients.” They recommend that a greater emphasis be placed on recruiting clinical trial patients with age demographics that better represent the median age of the advanced NSCLC population. n Reference 1. Sacher AG, Le LW, Leighl NB, et al: Elderly patients with advanced NSCLC in phase III clinical trials. J Thorac Oncol 8:366-368, 2013.

ference was seen among patients with nonsquamous tumors. n

Disclosure: Among the study investigators, Drs. Andrea Ardizzoni, Marcello Tiseo, Corrado Boni, Filippo de Marinis, Lucio Crinò, and Egbert F. Smit have received honoraria from Eli Lilly. All other authors reported no potential conflicts of interest.

References 1. Ardizzoni A, Tiseo M, Boni L, et al: Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non–small-cell lung cancer (NSCLC): Results of GOIRC 02-2006 randomized phase II study and pooled analysis with NVALT7 trial. J Clin Oncol 30:4501-4507, 2012. 2. Smit EF, Burgers SA, Biesma B, et al: Randomized phase II and pharmacogenetic study of pemetrexed compared with pemetrexed plus carboplatin in pretreated patients with advanced non–small-cell lung cancer. J Clin Oncol 27:2038-2045, 2009.

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Expert’s Corner

Finding New Strategies to More Effectively Treat Pancreatic Cancer A Conversation with Eileen M. O’Reilly, MD By Jo Cavallo

Eileen M. O’Reilly, MD

hile some progress has been made in understanding the molecular pathogenesis, genetic risk factors, and genomics of pancreatic adenocarcinoma, the disease remains one of the most challenging malignancies. According to Surveillance, Epidemiology, and End Results (SEER) figures, 44,000 people were diagnosed with pancreatic cancer in 2012 and 37,400 died from the disease. For most newly diagnosed patients, the 1-year survival rate is 20%, and the 5-year survival rate is 4%, the lowest for all types of malignancies. Finding strategies to detect the cancer at an earlier stage and investigating new therapeutic directions to improve overall survival in pancreatic cancer is a main focus of the research efforts of Eileen M. O’Reilly, MD, Associate Member of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center, Associate Professor of Medicine at Weill Cornell Medical College, and a member of the GI core committee of the Alliance for Clinical Trials in Oncology Foundation (formerly the CALGB Foundation). The ASCO Post talked with Dr. O’Reilly about the advancements being made in more precisely identifying individuals at risk and the outlook for developing more effective therapeutics.

Improving Survival What has to happen to improve survival rates for patients with pancreatic cancer? The two key things are to find better screening methods for earlier detection and to develop better treatment options. Perhaps the one that is likely to have the greatest impact is earlier identification of the disease. For most people, this cancer is diagnosed late and typically is either locally advanced and

inoperable or already metastatic, and treatments in that setting are noncurative in intent. To have a major impact in terms of outcomes, we need to be able to screen successfully and diagnose this disease earlier, and both of those are elusive challenges at the moment. Pancreatic cancer has a very high propensity for early spread. In fact, mouse models suggest that even in very small tumors at the primary site there are already evident metastases, and we see that same situation all too often in the clinical setting. Consequently, there is a focus on research in the setting of early diagnosis and screening.

Genetic Mutations What are some of the gene mutations involved in the development of pancreatic cancer? There are two main groups of mutations. There are the single-gene defects, which account for the minority of risk, and there is a larger group that involves

er lifetime risk of pancreatic cancer than the baseline population. There is no consensus yet regarding which populations of patients to screen, what is the best screening test, how often people should be screened, and what is the threshold for intervention—remembering that that threshold leads to a big undertaking, including a Whipple surgery or a total pancreatectomy.

Screening and Diagnostic Testing How would you screen healthy people for these gene mutations? Ideally, people in high-risk groups would be enrolled in a prospective registry and followed. That’s what is done at Memorial Sloan-Kettering Cancer Center (MSKCC) and at other major cancer centers. Research is aimed at determining the best tools with which to screen these patients. For example, clinical assessments such as cancer antigen (CA) 19-9 measurement have been

New directions in pancreatic cancer research are focusing on breaking down the complex physical barrier involved in primary tumors and enhancing drug delivery. —Eileen M. O’Reilly, MD

a complex genetic etiology whereby multiple genes may be affected, but those exact mutations are not known. One of the single-gene (mismatch repair) defects presents as hereditary nonpolyposis colorectal cancer, which affects a small percentage of people with pancreatic adenocarcinoma. PALB2 was more recently identified as a risk factor and probably accounts for less than 1% of the pancreatic cancer population in terms of genetic contribution. Another hereditary syndrome associated with pancreatic cancer is familial atypical mole malignant melanoma. Individually, these genetic factors can carry a relatively high risk of developing pancreatic cancer, but the overall frequency is very low. The most well known genetic link in terms of predisposition stems from mutations in BRCA1 and BRCA2. Carriers of mutations in these genes have a two- to fivefold high-

looked at but are mostly insensitive. As to diagnostic testing, CT with high-resolution contrast has been considered, but a theoretic concern is that you would be consigning healthy people to cumulative radiation exposure, so over the past decade the focus has been on MRI. If a specific abnormality is identified on MRI, that may trigger an endoscopic ultrasound to more fully evaluate the abnormality, followed by discussions with gastroenterologists and surgeons about whether to take that ultimate step to surgery. The area that hasn’t been fully explored yet is a form of chemoprevention or oncoprevention strategy. I think that is a fairly distant reality, but it is a future goal.

Current Research What areas of research are you currently involved in? We have a number of clinical trials

underway at MSKCC. One area of particular interest is the study of BRCA-related pancreatic cancer. These mutations affect a relatively small subset of patients, but in the Northeast we see a somewhat higher frequency of BRCA-related pancreatic cancer because New York has a large Ashkenazi Jewsh population, in which BRCA mutations are commonly found. Although about 5% to 7% of pancreatic cancer may develop as the result of the BRCA mutation in people of Ashkenazi heritage, about 10% to 15% may harbor an underlying mutation, and there is evidence that their pancreatic cancer may be more susceptible to the benefits of certain therapies. We have two clinical studies ongoing to understand as much as we can about BRCA-mutated pancreatic cancer in terms of its genetic makeup, the types of mutations, the frequency of the mutations that are present, and the mechanisms of resistance in the context of platinum-based therapy and poly(ADPribose) polymerase (PARP) inhibitors. Our studies are investigating whether combining a PARP inhibitor with a cytotoxic backbone of cisplatin and gemcitabine augments outcomes in patients with BRCA- or PALB2mutated pancreatic cancer and whether there is therapeutic value in using higher doses of a single-agent PARP inhibitor in patients with BRCA-mutated pancreatic cancer who have been previously treated. In the front-line setting, we are completing a dose-finding phase to determine the best dose of the investigational PARP inhibitor veliparib to combine with cisplatin and gemcitabine. Soon, we will go on to a randomized comparison of the addition of the PARP inhibitor to cisplatin and gemcitibine vs cisplatin and gemcitabine alone. We are also evaluating patterns of gene expressions and possible mutation reversions that might suggest sensitivity or resistance to these agents.

Surgical Techniques Are there new surgical techniques for this disease? Between 10% and 15% of all patients diagnosed with pancreatic cancer are eligible for surgery, and in that group, about 80% have tumors in the head of the pancreas and undergo a Whipple surgery.

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Expert’s Corner

Patients with tumors in the body or tail of the pancreas will usually have a distal pancreatectomy and splenectomy. Ongoing investigations are evaluating the use of robotically assisted surgical removal of pancreatic tumors, which is an emerging option, particularly for tail of pancreas malignancies. Another study is evaluating pasireotide (Signifor) to reduce the rates of leaks and fistula, two major complications postsurgery, and data are awaited.

On the Horizon Are advances in treatment for pancreatic cancer expected soon? A lot of research in treating pancreatic cancer is focused on drug delivery. Primary pancreatic tumors have a complex physical stromal-tumoral interaction that may preclude drugs from penetrating the tumor, and this is also true for radiation. New directions in research are focusing on breaking down this physical barrier and enhancing drug delivery, and multiple preclinical and clinical trials are underway to evaluate these concepts. With regard to therapeutics, FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin)—for patients who are robust enough to tolerate this regimen—has emerged as an active treatment for advanced pancreatic disease and is now being integrated into earlier-stage disease settings. At the 2013 Gastrointestinal Cancers Symposium, data were presented showing that the addition of nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) to gemcitabine significantly improved overall survival in treatment-naive patients with metastatic pancreatic cancer, compared with gemcitabine alone.1 This combination will likely provide a new backbone on which to add novel targeted agents and is anticipated to become increasingly integrated into treatment considerations for this disease. Immunotherapy is another area that is being extensively investigated in multiple settings in pancreatic cancer. Progress to date has been modest with regard to therapeutics, but new avenues evaluating anti-CTLA4, PD-1, PDL-1, anti-CD40, and novel vaccines are being developed.

Thoughts on Patient Care Is patient care improving, including end-of-life care? This is an extremely important topic in a disease that we can’t cure and where patients have a big symp-

tom burden, complex gastroenterologic problems, and issues in coming to terms with a difficult prognosis. We have completed a small pilot study for patients with advanced pancreatic cancer, using a video tool to help us better convey to patients what their end-of-life options might be. It also elicits their wishes in terms

of the level of medical care and support, and interventions they would choose to receive. This sort of tool provides new ways to assist communication and start discussions on sensitive topics related to advance care planning. n

Disclosure: Dr. O’Reilly receives research funding for NCI PARP studies from Celgene.

Reference 1. Von Hoff DD, Ervin TJ, Arena FP, et al: Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). 2013 Gastrointestinal Cancers Symposium. Abstract LBA148. Presented January 25, 2013.

The ASCO Post | MARCH 15, 2013

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Announcements

The Pancreatic Cancer Action Network Welcomes New Members to Its Medical Advisory Board

he Pancreatic Cancer Action Network has named four new members to the organization’s Medi-

cal Advisory Board. The newest advisors are leading clinicians in the field of pancreatic cancer: Joseph M.

Herman, MD, MSc, Johns Hopkins University; George A. Fisher Jr, MD, PhD, Stanford University; James

Farrell, MD, Yale University; and Philip Agop Philip, MD, PhD, Karmanos Cancer Institute. “I am pleased to welcome these distinguished leaders to our Medical Advisory Board. They bring a great wealth of expertise to the organization and their active participation will further strengthen our programs to support pancreatic cancer patients,” stated Julie Fleshman, President and CEO of the Pancreatic Cancer Action Network. “The role of the Medical Advisory Board is essential as the Pancreatic Cancer Action Network works to double the survival for pancreatic cancer by 2020.” The Medical Advisory Board includes clinicians who specialize in the care of people with pancreatic cancer. Other members of the Medical Advisory Board are: Jordan Berlin, MD, Chair, Vanderbilt-Ingram Cancer Center; Marcia Canto, MD, Johns Hopkins University; Christopher Crane, MD, MD Anderson Cancer Center; Jason Fleming, MD, MD Anderson Cancer Center; Jane Hanna, RN, OCN, Georgetown University Hospital; Mokenge Malafa, MD, Moffitt Cancer Center; Eileen O’Reilly, MD, Memorial Sloan-Kettering Cancer Center; Maria Petzel, RD, CSO, LD, CNSC, MD Anderson Cancer Center; Vincent Picozzi, MD, Virginia Mason Medical Center; Mark Pochapin, MD, New York University and Mark Talamonti, MD, NorthShore University HealthSystem. To learn more about the Pancreatic Cancer Action Network’s Medical Advisory Board, visit www.pancan.org. n

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PAGE 59

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Evaluating HER2 Status in Esophageal Cancers: FISH vs Immunohistochemistry By Caroline Helwick

n screening patients with esophageal cancers for HER2 status, the relative efficiency of immunohistochemistry (IHC) vs fluorescence in situ hybridization (FISH) has been debated. Researchers from the Mayo Clinic compared the testing strategies and have proposed an algorithm that puts IHC up front, with FISH restricted to cases with an indeterminate (2+) IHC score.1

method has its advantages. IHC is faster, less labor-intensive, and less expensive, while FISH is less vulnerable to tissue artifacts and offers a more objective scoring system, according to Dr. Yoon. Dr. Yoon and colleagues evaluated 673 surgically resected esophageal adenocarcinoma specimens for the concordance of HER2 testing between IHC and FISH, in a blinded manner using FDA-approved assays. A consensus IHC score was determined by two pathologists using tumor-specific criteria (negative, 0 or 1+; indeterminate, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17 (chromosome 17) ratio ≥ 2.

Results Harry H. Yoon, MD

Harry H. Yoon, MD, of the Department of Oncology, who presented the results at the 2013 Gastrointestinal Cancers Symposium, said, “Our findings support a testing algorithm for resected esophageal adenocarcinomas where IHC is used for initial screening, and FISH testing is restricted to cases with equivocal IHC results.” HER2 overexpression, a known driver of tumor aggressiveness in esophageal adenocarcinoma, is found in 7% to 22% of cases. For HER2positive patients, trastuzumab (Herceptin) improves survival; therefore, testing for HER2 is important.

Concordance between HER2 Testing Methods While exploratory research in upper digestive tumors has suggested that IHC is more predictive of trastuzumab benefit than FISH, the concordance between these two tests has not been established, and each testing

By FISH, 17% of tumors tested positive. By IHC, 13% tested positive, 25% were indeterminate (ie, 2+), 23% were negative by 1+, and 39% were negative by a 0 score. Among the 89 patients with IHC 3+ score, 79 were FISH-positive and 10 were FISH-negative. Of the 167 indeterminate (2+) patients, 21 were FISH-positive and 146 were FISHnegative. Of the 417 IHC-negative patients, 16 were FISH-positive and 401 were FISH-negative. This yielded a concordance rate of 95% between FISH and patients who were IHC 3+ or IHC-negative, and a 74% concordance rate when IHC 2+ patients were included. HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0 to 1+ cases. Accordingly, using FISH as the reference standard, the positive predictive value of a positive IHC test (3+) was 89%, and the negative predictive value of a negative test was 96%. Importantly, the positive predictive value

FISH vs IHC in Esophageal Cancer ■■ Mayo Clinic investigators found a concordance rate of 95% between FISH and patients who were IHC 3+ or IHC-negative, and a 74% concordance rate when IHC 2+ patients were included.

■■ The positive predictive value of an indeterminate IHC score (2+) for detecting HER2 amplification was 13%.

■■ They propose that patients first be tested by IHC, with FISH restricted to IHC 2+ cases.

EXPERT POINT OF VIEW

. Randolph Hecht, MD, Professor of Clinical Medicine and Director of the Gastrointestinal Oncology Program at the University of California, Los Angeles, commented to The ASCO Post that it is premature to accept this algorithm in the absence of its correlation with clinical outcomes. The one dataset that correlated HER2 status with outcomes is the ToGA trial, which established the benefit of treating HER2-positive patients with trastuzumab. “The data derived from ToGA was at least corJ. Randolph Hecht, MD related with outcomes,” he noted. “We need more datasets, and these will be coming out,” he said. One is the phase III TRIO013 (LOGiC) trial of lapatinib, oxaliplatin, and capecitabine in locally advanced or metastatic HER2-amplified gastric cancer, for which Dr. Hecht is the principal investigator.

Explanation of Discordant Results Needed What is confusing is that in breast cancer, FISH is known to be far more accurate than IHC in determining HER2 status, he pointed out. “That battle has been fought and won by FISH, which is the gold standard in breast cancer,” Dr. Hecht noted. “The question that comes up is, why this discordant result [with esophagogastric cancer in the ToGA trial]?” Dr. Hecht said he would like to have assurance of the quality of the FISH assays in the study, and would like to know what the numerators and denominators are for the FISH ratio of 2.0 for positivity. “In many breast cancer trials, if there is loss of chromosome 17q so that the denominator is lower, you may not truly have amplification, which is required to affect the biology of the tumor. Maybe some of the IHC 0 to 1+ FISH-positive patients in the ToGA trial were false-positives, and this could explain some of the discordance.” In addition, Dr. Hecht is concerned about a screening strategy that may overtreat some patients with an expensive drug and exclude others from treatment with an active relatively nontoxic agent. n Disclosure: Dr. Hecht has received research funding from GlaxoSmithKline and Roche.

of an indeterminate IHC score (2+) for detecting HER2 amplification was 13%, he said. “In the largest study to date comparing HER2 testing methods in esophageal adenocarcinoma, a negative IHC result nearly excludes the presence of gene amplification by FISH,” Dr. Yoon said. “A positive IHC result (3+) strongly predicts for the presence of amplification (89%), and an indeterminate IHC result (2+) is a weak predictor for amplification (13%).” “Ideally, the clinical impact of HER2 expression or amplification is best studied as a predictor of benefit from trastuzumab therapy,” he said. “However, the clinical data that can address this question more robustly than the ToGA trial [which established the benefit of adding trastuzumab to

chemotherapy for gastric cancer] are, at best, many years in the future. Our proposed algorithm is intended to serve as a helpful guide for clinicians in the meantime. Integrating our findings with ToGA data, we believe that IHC is the preferred screening test in surgical esophageal adenocarcinoma specimens to determine HER2 status, with referral to FISH restricted to cases with an indeterminate IHC score.” n Disclosure: Dr. Yoon has received honoraria and research funding from Genentech/Roche.

Reference 1. Yoon HH, Shi Q, Sukov WR, et al: HER2 testing in esophageal adenocarcinoma using parallel tissue-based methods. 2013 Gastrointestinal Cancers Symposium. Abstract 2. Presented January 24, 2013.

The ASCO Post | MARCH 15, 2013

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Oncogenic Pathway Signatures May Guide Treatment after Colorectal Cancer Resection By Caroline Helwick

eregulation of oncogenic signaling pathways was used to molecularly subclassify colorectal cancers into clinically relevant subgroups with both prognostic and predictive implications, in a study from the Duke Institute for Genome Sciences and Policy in Durham, North Carolina.1

with adjuvant chemotherapy,” said Joshua M. Uronis, PhD. The work was conducted in the laboratory of David Hsu, MD, PhD. At the 2013 Gastrointestinal Cancers Symposium, Dr. Uronis described the group’s effort to develop genetic biomarkers that are prognostic for recurrence, predictive of drug sensitivity, and applicable in both the primary and metastatic settings.

Study Design

Joshua M. Uronis, PhD

“There is a need to individualize therapy for colorectal cancer. A main challenge is determining which patients are at risk for recurrence after resection and who should be treated

The researchers compiled microarray data from 850 patients with primary colorectal cancer from four datasets, based on the activity of 19 oncogenic pathways, and used this information to generate unique patterns of pathway deregulation for each patient’s tumor. Six molecular subgroups of colorectal cancer were identified, and they differed significantly in their risk of recurrence. For example, while recurrencefree survival approached 100% for

Molecular Alterations in Colorectal Cancer ■■ Investigators described the activity of 19 oncogenic pathways in colorectal

cancer, and found that deregulation can be used to molecularly subclassify colorectal cancers into clinically relevant subgroups.

■■ These subgroups differ in recurrence risk and in drug sensitivity. ■■ The model may someday be useful in designing treatment for patients after resection for both primary and metastatic lesions.

molecular subgroup 4, it fell to about 40% for molecular subgroup 3 (P = .0004). A similar result was observed when the model was applied to the metastatic data set (P = .046). These patterns were then translated into gene-expression signatures and used to measure the probability of pathway activation in a panel of cell lines. Under this approach, the model proved predictive of response to certain drug treatments, Dr. Uronis reported. “We observed that [molecular subgroups] demonstrated differential sensitivity to specific targeted agents,

EXPERT POINT OF VIEW

illiam M. Grady, MD, of the Fred Hutchinson Cancer Research Center, Seattle, a member of the news planning team for the symposium, commented, “There has been considerable interest in determining

William M. Grady, MD

whether molecular alterations in primary colorectal cancer are more accurate prognostic indicators than the tumor’s pathologic stage, which is what is currently used. In this study, by grouping the molecular alterations that are present in colorectal cancers according to the signaling pathways

that they regulate, Dr. Uronis and colleagues have used a unique approach to identify molecular alterations that are predictive for recurrent cancer, not only for nonmetastatic disease but also for metastatic disease.” “If these results can be validated, these molecular alteration patterns have the potential to be used as markers to identify which patients should receive aggressive care after surgical resection of both primary and metastatic colorectal cancer and to direct the specific chemotherapeutic agents they should receive,” Dr. Grady predicted.

A Step Toward Personalized Medicine? Jordan Berlin, MD, Ingram Professor of Cancer Research and Clinical Director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center, Nashville, said several factors “make this study interesting,” including the potential to demonstrate differential

sensitivity to targeted agents according to subgroup, the use of the explant model (which maintains its characteristics across multiple generations), and the demonstration of activity with drugs such as mTOR inhibitors, which are not currently used in colorectal cancer. “The study is preliminary, and this needs further testing, but potentially we could use this model to identify targets to hit and agents that are effective in each subgroup,” he said. “While the investigators say they hope to use this approach in the adjuvant setting, I see it as very applicable to metastatic disease, where it will be easier to apply it sooner…. If clinical trials confirm what these preclinical models show, we may be able to treat subgroups of patients differently and, in some, with surprising drugs. This may move us toward the personalized medicine that we are all using as a buzzword now.” n

Disclosure: Drs. Grady and Berlin reported no potential conflicts of interest.

such as [subgroups] 1, 2, and 3 to inhibition of HER2 by lapatinib [Tykerb] and inhibition of the epidermal growth factor receptor by erlotinib [Tarceva] < .05),” he said. “From this we gath(P �� er that we can make basic predictions using pathway signatures.”

Patient-derived Explants The researchers’ next step was to design patient-derived colorectal cancer explants that formed the basis of a murine model of drug sensitivity. This model is being used to validate the findings. For example, the experiments have shown that molecular subgroups with high mTOR activity are highly sensitive to mTOR inhibitors, while those with low mTOR expression are resistant to these agents. “Currently, we have developed 50 independent explants,” he said. “This will allow for in vivo validation of the findings.” The findings suggest that prognostic and predictive biomarkers can be derived by combining a genomicbased molecular profile of colorectal cancer with a preclinical murine model of patient-derived colorectal cancer explants, he said. n

Disclosure: Dr. Uronis reported no potential conflicts of interest.

Reference 1. Uronis JM, VanDeusen JB, Datto MB, et al: A molecular profile of colorectal cancer to guide prognosis and therapy after resection of primary or metastatic disease. 2013 Gastrointestinal Cancers Symposium. Abstract 339. Presented January 26, 2013.

The dual role that integrins play on both tumor and endothelial cells may contribute to the aggressive nature of glioblastoma PRESENTING

THE

ROLE

I N T E G R I N S

in Glioblastoma

• Gliomas account for approxiately 80% of all malignant brain and central nervous system tumors in adults.1 Glioblastoma is the most aggressive form of gliomas.2 • Integrins are a family of at least 24 distinct cell surface heterodimer receptors. As cell surface receptors, integrins regulate cellular behavior by way of signal transmission between extracellular and intracellular spaces through interactions with extracellular ligands.3, 4, 5 • Integrins are overexpressed on tumor cells and vasculature but not widely expressed on normal tissues and blood vessels.3, 5 • The overexpression and activity of integrins are important for proliferation, migration, invasion, and survival of glioblastoma cells.3 Integrins also support tumor growth and progression by promoting tumor-associated angiogenesis.6 References 1. Central Brain Tumor Registry of the United States. http://www.cbtrus.org/2011-NPCR-SEER/ WEB-0407-Report-3-3-2011.pdf. Accessed October 6, 2011. 2. Louis DN, et al. Acta Neuropathol. 2007;114:97-109. 3. Desgrosellier JS, et al. Nat Rev Cancer. 2010;10:9-22. 4. Hynes RO. Cell. 2002;110:673-87. 5. Lu X, et al. Perspect Medicin Chem. 2008;2:57-73. 6. Tabatabai G, et al. Target Oncol. 2010;5:175-81.

To view an informative animation on the role of integrins in GBM, please visit our website at www.emdserono.integrins.com

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The ASCO Post | MARCH 15, 2013

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News Breast Cancer

Subsets of Young Patients Have Higher Pathologic Complete Response Rates By Caroline Helwick

n achieving a pathologic complete response to neoadjuvant chemotherapy, it seems that age matters, according to a study reported at the 2012 San Antonio Breast Cancer Symposium.1 Patients with breast cancer aged 35 and younger were more likely to achieve a pathologic complete response than their older counterparts. The finding was confined, however, to those with triple-negative and luminal-type tumors, German investigators reported. “In these patients, [pathologic complete response] was associated with a good prognosis,” said Sibylle Loibl, MD, PhD, Associate Professor at the University of Frankfurt in Germany. “Breast tumors that arise in young women seem to be a special biological entity.” The study evaluated data from eight German studies that included 8,949 women with operable or locally advanced, nonmetastatic breast cancer who were treated with neoadjuvant chemotherapy. Researchers compared pathologic complete response and disease-free survival for the subgroup of 704 women aged 35 or younger to those of older women. Compared to the older cohort, the younger subgroup included a greater proportion of triple-negative tumors (32%) than women aged 36 to 50 (25%) or 51 years and older (21%) and a smaller proportion of luminal-A tumors. Hormone receptor–positive/HER2-negative tumors were the case for 35% of the young women, vs 48% of women aged 36 to 50 and 51% of the oldest cohort, she said.

Findings by Age and Subtype “Age was an independent predictive factor for [pathologic complete response],” Dr. Loibl announced. Disease-free survival and local recurrencefree survival were also age-related, though no significant differences were observed in overall survival. The pathologic complete response rate rate was 23.8% for the very young women, vs 17.5% for women aged 36 to 50 and 13.5% for those aged 51 and older (P < .001). Further analysis revealed that this difference was confined to tumors that were triple-negative and hormone receptor–positive/HER2-negative. Compared to women aged 36 to 50 years, disease-free survival was signifi-

cantly worse for women ≤ 35 (HR = 0.83; P =.031) as was local recurrencefree survival (HR = 0.74; P = .018). “However, women aged 35 and younger with hormone receptor– positive/HER2-negative tumors who achieved a [pathologic complete response] had a better disease-free survival than younger women who did not achieve a [pathologic complete response],” Dr. Loibl noted. Altogether, according to age there was no difference in disease-free survival when the patients achieved a pathologic complete response, but patients without a pathologic complete response had significantly worse disease-free survival if they were 35 or younger, she summed up. “In the neoadjuvant setting, [pathologic complete response] matters,” Dr. Loibl emphasized. “The results of not achieving a [pathologic complete response] are striking. The very young have a 25% increased risk for relapse over their older counterparts, the risk for local recurrences is 33% higher, and there is a

Breast Cancer in Very Young Women ■■ The achievement of a pathologic complete response is more likely among

patients aged 35 and younger than among older women, at least for those with triple-negative or luminal-type tumors.

■■ There was no age-related difference in disease-free survival when patients

achieved a pathologic complete response, but this outcome was worse for the very young patients when they did not achieve a pathologic complete response.

■■ Breast cancer in very young women may be biologically different from those aged 35 and older.

trend for worse overall survival as well.” Importantly, patients with triple-negative disease who achieved a pathologic complete response had “excellent survival” irrespective of their age, she added. “In contrast to other analyses, very young women with hormone receptor–positive/HER2-negative tumors benefited from a [pathologic complete response] in this study,” she said. “There is a benefit long-term with a [pathologic complete response], even in this biologically good subgroup. This young sub-

set, therefore, where [pathologic complete response] really matters, should be considered for neoadjuvant chemotherapy,” she maintained. n

Disclosure: Dr. Loible reported no potential conflicts of interest.

Reference 1. Loibl S, Jackisch C, Gade S, et al: Neoadjuvant chemotherapy in the very young, 35 years of age or younger. 2012 San Antonio Breast Cancer Symposium. Abstract S31. Presented December 6, 2012.

EXPERT POINT OF VIEW

aura J. van ’t Veer, PhD, Leader of the Breast Oncology Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, commented on the findings. “These investigators confirm in a robust meta-analysis that neoadjuvant chemotherapy response is different for subgroups identified by standard immunohistochemical markers for estrogen, progesterone receptor, and HER2, and this is helpful. They also showed that we need to further examine the biology of the tumors that arise in younger women,” she said. “I have done much work on the MammaPrint signature in tumors of younger as well as older patients, and we see that age is less of an independent

Laura J. van ’t Veer, PhD

marker in these women, but that the proportion of biological high risk vs low risk varies by age group.” Dr. van ’t Veer asked the investigators whether they had data on which tumors were screen-detected, but Dr. Loibl said that information is not available on this study population. Dr. van ’t Veer explained that screen-detected cancers in the older women are typically associated with a lower risk of recurrence. “These patients are at ultralow risk,” Dr. van ’t Veer noted. “When you compare the young women with the older ones, you need to keep this in mind as well,” she suggested.

Alternative Hypotheses Andrew Seidman, MD, Attending Physician for the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York, questioned whether the younger patients got fuller doses of chemotherapy on time and on schedule as compared to older patients. “Data in all subsets of the younger women could be influenced by drug delivery, ie, dose intensity,” he pointed out. He further offered hypotheses for the finding that pathologic complete respons-

Andrew Seidman, MD

es in estrogen receptor–positive/HER2negative patients correlated with improved overall survival only in the younger patients, not the older ones. “This leads one to wonder if ovarian failure/amenorrhea/ early menopause correlates with improved survival,” he suggested. “An alternative hypothesis is that luminal A breast cancers in very young patients, as opposed to older patients, have other signaling pathways that are important,” he said, “and these may be perturbed to a greater degree by cytotoxic chemotherapy.” n

Disclosure: Dr. van ’t Veer is cofounder, stockholder, and part-time employee of Agendia Inc, Irvine, California. Dr. Seidman reported no potential conflicts of interest.

ASCOPost.com | MARCH 15, 2013

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News Breast Cancer

21-gene Recurrence Score Does Not Predict Paclitaxel Benefit By Caroline Helwick

he 21-gene recurrence score significantly predicted the risk of recurrence and death in nodepositive, estrogen receptor–positive patients treated with adjuvant chemoendocrine therapy, but it did not predict benefit from the addition of paclitaxel to the regimen in a subset of patients from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial,1 according to Eleftherios (Terry) P. Mamounas, MD, MPH, FACS, Professor of Surgery at Northeastern Ohio Universities College of Medicine and Medical Director of

EXPERT POINT OF VIEW

lifford A. Hudis, MD, Chief of the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York, commented after the presentation, “It strikes me that these findings are parallel to those shown with PAM50 by Liu et al at this meeting.” In that study,1 based on the Cancer and Leukemia Group B (CALGB) 9741 population, intrinsic molecular subtype did not predict for improved survival with dose-dense vs standard chemotherapy. The authors hypothesized that this is because the prognostic differences by subtype outweighed the modest but significant clinical benefit of dose-dense chemotherapy for the overall population.

Questions Remain

Eleftherios (Terry) P. Mamounas, MD

the Comprehensive Breast Program at MD Anderson Cancer Center, Orlando, Florida, and Chairman of the Breast Committee of the NSABP Operations and Biostatistical Center, Pittsburgh, Pennsylvania.

Study Goals The goal of this substudy was to evaluate the recurrence score as a predictor of the risk of local-regional recurrence in node-positive, estrogen receptor–positive patients treated with adjuvant endocrine therapy and chemotherapy. The secondary goal was to evaluate recurrence score as a prognostic factor of outcome and as a predictive factor of benefit from the addition of paclitaxel (T) to doxorubicin/ cyclophosphamide (AC).

“The similarity relates to the fact that you have positive clinical trials, but you only have [tissue] from a subset, and though you see the same numerical trend, it is not statistically significant. This reflects the challenges inherent in planning studies retrospectively. The concern is that we could be missing a positive signal, just because of the statistics.” Daniel F. Hayes, MD, the StuNSABP B-28 compared AC vs AC-T in 3,060 node-positive patients.2 After 5 years, the addition of paclitaxel significantly reduced the annual hazard for disease-free survival events by 17% in the entire population (P = .006). The current study subgroup included 1,065 estrogen receptor–positive, tamoxifen-treated patients for whom recurrence score was generated, followed for a median of 11.2 years. The recurrence score distribution in this cohort was low in 36%, intermediate in

Recurrence Score and Paclitaxel Benefit ■■ The 21-gene recurrence score significantly predicted risk of recurrence

and death in node-positive, estrogen receptor–positive patients treated with adjuvant chemoendocrine therapy, but it did not predict benefit from the addition of paclitaxel to the regimen in a subset of patients from NSABP B-28.

■■ The overall benefit from paclitaxel in the study cohort was small, and there was low power to detect a treatment-by–recurrence score interaction.

art B. Padnos Professor in Breast Cancer Research at the University of Michigan, Ann Arbor, commented for The ASCO Post. “It is not clear what to make of these data. At the least, they are consistent with what we published from Clifford A. Hudis, MD Daniel F. Hayes, MD CALGB protocol 9344,2 in which paclitaxel was beneficial is open and we have nearly 1,000 pawhen added to [doxorubicin/cyclo- tients already on the randomized part phosphamide] adjuvant chemother- of the study,” Dr. Hayes noted. n Disclosure: Drs. Hudis and Hayes reported apy in all groups except those with no potential conflicts of interest. estrogen receptor–positive, HER2negative cancers,” he told The ASCO Post. “However, there is still sub- Reference 1. Liu MC, Pitcher BN, Mardis ER, stantial confusion as to whether the biology of the cancer can predict re- et al: PAM50 gene signature is prognossponse to all types of chemotherapy tic for breast cancer patients treated with or specific types, such as paclitaxel.” adjuvant anthracycline and taxane-based He said the data provide further chemotherapy. 2012 San Antonio Breast Cancer Symposium. Abstract P2-10-01. impetus for clinicians to support Presented December 5, 2012. Southwest Oncology Group (SWOG) 2. Henderson IC, Berry DA, Demetri S1007, in which node-positive pa- GD, et al: Improved outcomes from addtients with estrogen receptor–positive ing sequential paclitaxel but not from estumors and recurrence score < 25 will calating doxorubicin dose in an adjuvant be randomly assigned to chemothera- chemotherapy regimen for patients with py vs no chemotherapy; all will receive node-positive primary breast cancer. J standard endocrine therapy. “This trial Clin Oncol 21:976-983, 2003. 34% and high in 30%. Older patients and patients with small tumors were significantly more likely to have a low recurrence score. The recurrence score was significantly correlated with disease-free survival, distant recurrence-free survival, breast cancer–specific survival, and overall survival, and was prognostic regardless of the number of positive nodes (reported at the 2012 Breast Cancer Symposium).3 The ability to predict local-regional recurrence will be presented at the Society for Surgical Oncology 2013 meeting.

Minor Paclitaxel Benefit In San Antonio, Dr. Mamounas reported that the recurrence score failed to predict the benefit of adding paclitaxel, which offered minor benefit in this study population. “The overall benefit from paclitaxel in the study cohort was small, and there was low power to detect treat-

ment-by-[recurrence score] interaction,” he said. “We saw this first in the whole B-28 estrogen receptor–positive subgroup (n = 2,007) and then in the subgroup with [recurrence score] data (n = 1,065).” The hazard ratios for endpoints ranged from 0.86 to 0.90 for the whole B-28 subgroup and from 0.87 to 0.89 for the recurrence score analysis. While some of the risk reduction was statistically significant in the overall subgroup, the differences were small and were similar to the non–statistically significant differences in the recurrence score analysis. Absolute differences in disease-free survival, distant relapse-free interval, and overall survival ranged from 3% to 5% with the addition of paclitaxel, and were not statistically significontinued on page 66

For the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel. Contraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving

Important Safety Information

AND... • 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53-0.75])1 • XTANDI can be taken with or without food1 • Patients were allowed, but not required, to take glucocorticoids1 – In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1 • Oral, once-daily dosing1 • The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, diarrhea, arthralgia, hot ﬂush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of References: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.1.2013. © National Comprehensive Cancer Network, Inc 2012. All rights reserved. Accessed December 20, 2012. To view the most recent and complete version of the guidelines, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1 • The most common adverse reactions (≥ 10%) in patients treated with XTANDI were asthenia/fatigue, peripheral edema, back pain, arthralgia, musculoskeletal pain, diarrhea, hot ﬂush, headache, and upper respiratory tract infection1

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include enzalutamide (XTANDI) with a category 1 recommendation for use following docetaxel in patients with mCRPC.2

XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring. Please see adjacent pages for brief summary of Full Prescribing Information.

L Learn earn m more ore a att X XtandiHCP.com tandiHCP.com

The ASCO Postâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MARCH 15, 2013

PAGE 66

News

Recurrence Score and Paclitaxel Benefit continued from page 63

cant, though these were small numbers of patients, he said.

Recurrence Score Subgroups By recurrence score group, there were no significant differences in

any endpoints, although a nonsignificant trend for benefit was observed in patients with intermediate recurrence score and high recurrence score. For overall survival, patients with intermediate recurrence score who received paclitaxel had a nonsignificant 26% reduction in risk (PÂ =Â .12).

â&#x20AC;&#x153;For all three endpoints, and for the low, intermediate and high [recurrence score] groups, the interaction P values [for treatment effect] were not significant,â&#x20AC;? he reported. â&#x20AC;&#x153;In some clinicopathologic categories, significant benefit was observed for adding paclitaxel, but again, the test of interaction was not statistically significant.â&#x20AC;?

An exploratory analysis of the HER2-negative/equivocal subset (nÂ =Â 937, by HER2 gene expression in the 21-gene panel assay) showed that the prognostic effect of the recurrence score for all endpoints was not driven by HER2 positivity. â&#x20AC;&#x153;The [recurrence score] was not a significant predictor of benefit from the addition of pacli-

(continued) Table 1. Adverse Reactions in the Randomized Trial XTANDI N = 800 Grade 1-4 Grade 3-4 (%) (%)

XTANDIÂŽ (enzalutamide) capsules for oral use Initial U.S. Approval: 2012 BRIEF SUMMARY OF PRESCRIBING INFORMATION The following is a brief summary: please see the package insert for full prescribing information. ------------------------------ INDICATIONS AND USAGE ----------------------------XTANDI is indicated for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel. --------------------------------- CONTRAINDICATIONS ------------------------------Pregnancy XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss >VHH 8VH LQ 6SHFLÂżF 3RSXODWLRQV@. -------------------------- WARNINGS AND PRECAUTIONS ------------------------Seizure In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS ------------------------------Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĂ&#x20AC;HFW WKH UDWHV REVHUYHG in practice. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4. 7KH PRVW FRPPRQ DGYHUVH GUXJ UHDFWLRQV Â&#x2022; UHSRUWHG LQ SDWLHQWV UHFHLYLQJ XTANDI in the randomized clinical trial were asthenia/fatigue, back pain, GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO HGHPD PXVFXORVNHOHWDO SDLQ KHDGDFKH upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse UHDFWLRQV ZHUH UHSRUWHG DPRQJ RI ;7$1', WUHDWHG SDWLHQWV DQG RI placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the UDQGRPL]HG FOLQLFDO WULDO WKDW RFFXUUHG DW D Â&#x2022; DEVROXWH LQFUHDVH LQ IUHTXHQF\ LQ the XTANDI arm compared to the placebo arm. Table 1. Adverse Reactions in the Randomized Trial XTANDI Placebo N = 800 N = 399 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 (%) (%) (%) (%) General Disorders 9.0 44.4 9.3 Asthenic Conditionsa Peripheral Edema 1.0 13.3 0.8 Musculoskeletal And Connective Tissue Disorders Back Pain 26.4 24.3 4.0 Arthralgia 17.3 1.8 Musculoskeletal Pain 1.3 0.3 Muscular Weakness 9.8 6.8 1.8 Musculoskeletal 2.6 0.3 0.3 0.0 Stiffness

Placebo N = 399 Grade 1-4 Grade 3-4 (%) (%)

Gastrointestinal Disorders Diarrhea 21.8 1.1 0.3 Vascular Disorders Hot Flush 20.3 0.0 10.3 0.0 Hypertension 6.4 2.1 2.8 1.3 Nervous System Disorders Headache 12.1 0.9 0.0 Dizzinessb Spinal Cord 7.4 6.6 3.8 Compression and Cauda Equina Syndrome Paresthesia 6.6 0.0 0.0 4.3 0.3 1.8 0.0 Mental Impairment Disordersc Hypoesthesia 4.0 0.3 1.8 0.0 Infections And Infestations 10.9 0.0 0.3 Upper Respiratory Tract Infectiond Lower Respiratory 2.4 4.8 1.3 Tract And Lung Infectione Psychiatric Disorders Insomnia 8.8 0.0 6.0 Anxiety 0.3 4.0 0.0 Renal And Urinary Disorders Hematuria 6.9 1.8 1.0 Pollakiuria 4.8 0.0 0.0 Injury, Poisoning And Procedural Complications Fall 4.6 0.3 1.3 0.0 Non-pathologic 4.0 1.4 0.8 0.3 Fractures Skin And Subcutaneous Tissue Disorders Pruritus 3.8 0.0 1.3 0.0 Dry Skin 0.0 1.3 0.0 Respiratory Disorders Epistaxis 3.3 0.1 1.3 0.3 a Includes asthenia and fatigue. b Includes dizziness and vertigo. c Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention. d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis, pharyngitis, and laryngitis. e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung infection. Laboratory Abnormalities ,Q WKH UDQGRPL]HG FOLQLFDO WULDO *UDGH QHXWURSHQLD RFFXUUHG LQ RI patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both DUPV RI SDWLHQWV RQ ;7$1', DQG RQ SODFHER H[SHULHQFHG *UDGH thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on ;7$1', *UDGH DQG RI SDWLHQWV RQ SODFHER *UDGH Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. Infections In the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related Injuries In the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas. Hallucinations In the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioidcontaining medications at the time of the event. Hallucinations were visual, WDFWLOH RU XQGHÂżQHG

ASCOPost.comâ&#x20AC;&#x201A; | â&#x20AC;&#x201A; MARCH 15, 2013

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taxel to AC in the HER2-negative/ equivocal patients,â&#x20AC;? he said. Dr. Mamounas concluded that the recurrence score does not predict benefit from adding paclitaxel to AC, possibly because â&#x20AC;&#x153;the overall benefit from paclitaxel in the study cohort was small and there was low power to detect treatment-by-

[recurrence score] interaction.â&#x20AC;? n

Disclosure: Dr. Mamounas has served as a paid consultant and speaker for Genomic Health Inc.

References 1. Mamounas EP, Tang G, Paik S, et al: Association between the 21-gene recurrence score and benefit from addition of adjuvant paclitaxel in node-positive, ER-

positive breast cancer patients: Results from NSABP B-28. 2012 San Antonio Breast Cancer Symposium. Abstract S110. Presented December 5, 2012. 2. Mamounas EP, Bryant J, Lembersky B, et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol

23:3686-3696, 2005. 3. Mamounas EP, Tang G, Paik S, et al: Prognostic impact of the 21-gene recurrence score on disease-free and overall survival of node-positive, ER-positive patients with breast cancer treated with adjuvant chemotherapy: Results from NSABP B-28. 2012 Breast Cancer Symposium. Abstract 1. Presented September 13, 2011.

Contact

MEDPC9886 - Xtandi Brief PI Colors: 4CP Trim/live: DO NOT PRINT Bleed: 8.625"w Ă&#x2014; 11.375"h Trim: 8.125"w Ă&#x2014; 10.875"h Output @ 100% Giant Creative Strategy Live: 7"w Ă&#x2014; 10"h

----------------------------------DRUG INTERACTIONS ------------------------------Drugs that Inhibit or Induce CYP2C8 &R DGPLQLVWUDWLRQ RI D VWURQJ &<3 & LQKLELWRU JHPÂżEUR]LO LQFUHDVHG the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI >VHH 'RVDJH DQG $GPLQLVWUDWLRQ DQG &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended >VHH &OLQLFDO 3KDUPDFRORJ\@ Drugs that Inhibit or Induce CYP3A4 Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers >VHH &OLQLFDO 3KDUPDFRORJ\ @ The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated LQ YLYR. Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g., ERVHQWDQ HIDYLUHQ] HWUDYLULQH PRGDÂżQLO QDIFLOOLQ DQG 6W -RKQÂśV :RUW PD\ DOVR reduce the plasma exposure of XTANDI and should be avoided if possible >VHH &OLQLFDO 3KDUPDFRORJ\ @. Effect of XTANDI on Drug Metabolizing Enzymes Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring >VHH &OLQLFDO 3KDUPDFRORJ\ @. -------------------------- USE IN SPECIFIC POPULATIONS -----------------------Pregnancy- Pregnancy Category X >VHH &RQWUDLQGLFDWLRQV@ XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI. Nursing Mothers XTANDI is not indicated for use in women. It is not known if enzalutamide is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent ZHUH DQG RYHU ZKLOH SHUFHQW ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV in safety or effectiveness were observed between these patients and younger SDWLHQWV 2WKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂżHG GLIIHUHQFHV LQ responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment A dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy YROXQWHHUV QR VLJQLÂżFDQW GLIIHUHQFH LQ HQ]DOXWDPLGH FOHDUDQFH ZDV REVHUYHG LQ SDWLHQWV ZLWK SUH H[LVWLQJ PLOG WR PRGHUDWH UHQDO LPSDLUPHQW P/ PLQ Â&#x201D; FUHDWLQLQH FOHDUDQFH >&U&/@ Â&#x201D; P/ PLQ FRPSDUHG WR SDWLHQWV DQG YROXQWHHUV ZLWK EDVHOLQH QRUPDO UHQDO IXQFWLRQ &U&/ Â&#x2022; P/ PLQ 1R LQLWLDO GRVDJH adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@. Patients with Hepatic Impairment A dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed >VHH &OLQLFDO 3KDUPDFRORJ\@

-------------------------------------- OVERDOSAGE -------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general VXSSRUWLYH PHDVXUHV WDNLQJ LQWR FRQVLGHUDWLRQ WKH KDOI OLIH RI GD\V ,Q D GRVH escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the LQ YLWUR mouse lymphoma thymidine kinase (Tk) gene mutation assay or the LQ YLYR mouse micronucleus assay. %DVHG RQ QRQFOLQLFDO ÂżQGLQJV LQ UHSHDW GRVH WR[LFRORJ\ VWXGLHV ZKLFK ZHUH consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy RI WKH SURVWDWH DQG VHPLQDO YHVLFOHV ZDV REVHUYHG DW Â&#x2022; PJ NJ GD\ HTXDO to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed DW Â&#x2022; PJ NJ GD\ WLPHV WKH KXPDQ H[SRVXUH EDVHG RQ $8& PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (PATIENT INFORMATION). Â&#x2021; ,QVWUXFW SDWLHQWV WR WDNH WKHLU GRVH DW WKH VDPH WLPH HDFK GD\ RQFH GDLO\ XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules. Â&#x2021; ,QIRUP SDWLHQWV UHFHLYLQJ D *Q5+ DQDORJ WKDW WKH\ QHHG WR PDLQWDLQ WKLV treatment during the course of treatment with XTANDI. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', KDV EHHQ DVVRFLDWHG ZLWK DQ LQFUHDVHG risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ FDXVH GL]]LQHVV PHQWDO LPSDLUPHQW paresthesia, hypoesthesia, and falls. Â&#x2021; ,QIRUP SDWLHQWV WKDW WKH\ VKRXOG QRW LQWHUUXSW PRGLI\ WKH GRVH RU VWRS ;7$1', ZLWKRXW ÂżUVW FRQVXOWLQJ WKHLU SK\VLFLDQ ,QIRUP SDWLHQWV WKDW if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day. Â&#x2021; $SSULVH SDWLHQWV RI WKH FRPPRQ VLGH HIIHFWV DVVRFLDWHG ZLWK ;7$1', DVWKHQLD IDWLJXH EDFN SDLQ GLDUUKHD DUWKUDOJLD KRW Ă&#x20AC;XVK SHULSKHUDO edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. Â&#x2021; ,QIRUP SDWLHQWV WKDW ;7$1', PD\ EH KDUPIXO WR D GHYHORSLQJ IHWXV Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

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ONCOLOGY

The ASCO Post | MARCH 15, 2013

PAGE 68

News Breast Cancer

Role of Sentinel Node Surgery Explored in Node-positive Breast Cancer Sentinel node procedure is 91% accurate in staging nodes after neoadjuvant chemotherapy in patients with node-positive disease at presentation. By Caroline Helwick

entinel lymph node surgery performed after neoadjuvant chemotherapy in women presenting with node-positive disease could spare many patients with breast cancer needless axillary lymph node dissection, according to a study of the American College of Surgeons Oncology Group presented at the 2012 San Antonio Breast Cancer Symposium (ACOSOG Z1071).1 “We showed that sentinel lymph node surgery correctly identified the nodal status in 91.2% of patients who

were node-positive at presentation and who underwent neoadjuvant chemotherapy,” said Judy C. Boughey, MD, of the Mayo Clinic, Rochester, Minnesota. Based on the factors that were shown to be associated with the lowest risk of false-negatives, Dr. Boughey said she would “feel safe incorporating sentinel node surgery in clinical practice in cases where patients have a good clinical response to chemotherapy, undergo sentinel node mapping with standardization of the technique, and have three or more sentinel nodes identified. I feel the false-negative rate is acceptable in that group.”

EXPERT POINT OF VIEW

esponding to the results of the ACOSOG Z1071 study, Seema A. Khan, MD, Professor of Surgery at Northwestern University Feinberg School of Medicine, Chicago, urged caution in adopting the practice of sentinel lymph node surgery after chemotherapy for some patients with breast cancer at this time. “It is always a little hard to interpret a registry study, as there is no comparison group, but the strategy that was tested in this study reflects an imSeema A. Khan, MD portant question: Do women with known nodal disease prior to neoadjuvant chemotherapy need to have their lymph nodes removed, or could they just have a sentinel biopsy?” she told The ASCO Post. The latter approach does provoke concern, she maintained. “The reason people worry about this is that we know that response to chemotherapy is not uniform. You could have some sites that respond to treatment and others that don’t. You can have a great response in the breast and less response in the axillae. For example, a patient with several nodes invloved prior to chemotherapy may respond well in the sentinel node, but not in all nodes,” she explained.

Study Limitations Dr. Khan was also concerned that the 12.4% false-negative rate exceeded the study’s prespecified goal of 10%, and that the conclusions regarding the number of sentinel nodes required for accuracy were based on what appears to be an unplanned analysis. “The factors that were associated with low false-positive rates such as clip placement and number of sentinel nodes removed were not hypothesized a priori. It was a post hoc analysis, and the upper end of the confidence interval was almost 17%. I worry about leaving disease behind in the axilla and not obtaining information that may be valuable in guiding radiotherapy plans. Although we learned from ACOSOG Z0011 that residual axillary disease is rarely followed by recurrence, all the women in that trial subsequently received chemotherapy, whereas in this study they had already had chemotherapy (though some would also receive endocrine therapy),” she said. “My overall take on ACOSOG Z1071 is that there are several important caveats that may be open to misinterpretation in the application of the data.” n Disclosure: Dr. Khan reported no potential conflicts of interest.

Sentinel Node Surgery after Neoadjuvant Chemotherapy ■■ ACOSOG Z1071 asked whether sentinel node surgery could take the place of axillary dissection for nodal staging in patients with node-positive breast cancer who underwent neoadjuvant chemotherapy.

■■ The strategy correctly identified nodal status in 91.2% of patients. ■■ The overall rate of false-negatives was 12.6%, but the rate was lower when the procedure used a dual tracer, and when at least three nodes were removed.

Study Questions and Details Sentinel lymph node surgery is routinely used for patients initially diagnosed with node-negative disease. The study evaluated whether it could be safely used in patients with node-positive breast cancer who are treated with neoadjuvant chemotherapy, most of whom undergo axillary node dissection. “The question is whether removal of the lymph nodes with an axillary dissection is needed, or whether less-invasive surgery would reliably identify patients who still have disease in the lymph nodes and which patients have converted to negative nodes,” she said. “Our hypothesis was that sentinel node surgery is an accurate method of axillary staging in these patients.” The primary endpoint was the false-negative rate for sentinel node surgery in patients who had at least two sentinel nodes examined, the expectation being that the rate would be 10% or lower, she said.

Subset of Interest The multicenter study included 756 patients with node-positive breast cancer who received neoadjuvant chemotherapy. Of these, 637 underwent both sentinel lymph node surgery and axillary dissection. Sentinel node surgery correctly identified the nodal status in 91.2% of patients, including 255 (40%) who were ultimately node-negative and 382 (60%) who had residual nodal disease—which was the subset of interest in the study. Of these 382 patients, axillary dissection confirmed that 326 were indeed sentinel node–positive, while 56 patients were sentinel node–negative but node-positive according to the axillary dissection. Sentinel node surgery, therefore, correctly identified the nodal status in 91.2% of patients. Among the 310 patients fitting the criteria for the primary endpoint—those

with clinical N1 disease who had at least two sentinel nodes examined—39 had negative sentinel nodes, yielding a falsenegative rate of 12.6% (95% probability = 9.4%–16.7%), Dr. Boughey reported.

Judy C. Boughey, MD

Lower False-negative Rates The false-negative rate was lower when both blue dye and radiolabeled colloid were used (10.8%; P = .046), and when at least three sentinel nodes were examined (9.1%; P = .004). The falsenegative rate was 21.1% with two nodes examined, 9.0% with three nodes, 6.7% with four nodes, and 11.0% with five or more nodes examined, she said. Of the 78 patients with clinical N1 disease who had only one sentinel node examined, 24 had no residual nodal disease, while 17 of the 54 with residual nodal disease had false-negative sentinel node findings, producing a false-negative rate of 31.5% in this group, she added. When histologic changes consistent with therapy effect were present, as was the case for 35.5% of patients, the false-negative rate was 10.8%. When therapy effect was not documented, the rate was 13.5%. When a clip was placed in positive lymph nodes at diagnosis, as was done for 32.8% of patients, the false-negative rate dropped to 7.4% among patients where the clip was found in the sentinel lymph node(s). There was no continued on page 69

ASCOPost.com | MARCH 15, 2013

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News Breast Cancer

Black Women Less Likely to Get Sentinel Lymph Node Biopsy and More Likely to Have Lymphedema on Axillary Lymph Node Dissection By Alice Goodman

lthough sentinel lymph node biopsy is the recommended method for axillary staging of node-negative breast cancer, racial disparities in access to care were found in a study presented at the 2012 San Antonio Breast Cancer Symposium. Black women were 12% less likely than white women with breast cancer to receive sentinel lymph node biopsy for axillary staging. Additionally, black women were twice as likely as white women to develop lymphedema when undergoing axillary lymph node dissection compared to patients having a sentinel node biopsy, the study found. “These findings emphasize the need

Dalliah M. Black, MD

for continuing dissemination of national practice guidelines for breast cancer to surgeons and other breast cancer providers in our communities,” stated lead author Dalliah M. Black, MD, Assistant Professor at The University of Texas MD Anderson Cancer Center in Houston.

SEER-Medicare Data The study utilized data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to

determine patterns of care—specifically, whether there was a difference in the utilization of sentinel lymph node biopsy in black patients compared with whites, and whether this difference had an influence on risk of lymphedema. The study sample was 31,274 women aged 66 or older; 1,767 were black, 27,856 were white, and 1,651 were “race unknown.” Overall, sentinel lymph node biopsy was used in 62% of black women and 65% of other nonwhite patients, compared with 74% of white women (P < .001 for both comparisons). Although the rate of sentinel lymph node biopsy increased from 2002 to 2007, the magnitude of racial disparity was similar throughout this period. In an analysis adjusted for patient characteristics, tumor size, and type of surgery, blacks remained 33% less likely to undergo the procedure. By 2007, when sentinel lymph node biopsy was recommended in the National Comprehensive Cancer Network (NCCN) guidelines, it was performed in 83% of whites vs 70% of blacks. Sociodemographic factors such as a patient residing in lower-income or lower-education regions and residing in areas with fewer surgeons were associated with lower sentinel lymph node biopsy receipt.

Lymphedema Rates The disparity in access to sentinel lymph node biopsy affected rates of lymphedema, Dr. Black continued. The 5-year cumulative incidence of lymphedema was 18% in black women and 12.2% in white women who underwent complete axillary lymph node dissection (P < .001). Among those who got sentinel

Disparities in Access to Sentinel Node Biopsy ■■ In a study of linked SEER and Medicare databases, blacks were less likely than whites to be treated with sentinel lymph node biopsy for axillary staging.

■■ Lymphedema was twice as likely to develop in black women treated with complete axillary lymph node dissection, but rates of lymphedema were similar in both racial groups treated with sentinel lymph node biopsy.

Sentinel Node Surgery continued from page 68

statistically significant difference according to clinical T stage. For the 34 patients with clinical N2 disease, there were no false-negatives, she reported. “We conclude that sentinel lymph node surgery is a useful tool for the

detection of residual nodal disease in women with node-positive disease receiving neoadjuvant chemotherapy, but surgical technique is important for minimizing the false-negative rate,” Dr. Boughey said. “Use of a dual tracer and resection of at least two sentinel nodes is important. Clip placement may help

EXPERT POINT OF VIEW

“T

his study confirms previously published racial disparities in access to care, but factors that drive these disparities have not been elucidated,” stated Elizabeth Mittendorf, MD, Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston. The study was conducted through 2007, and even at that time there were hospitals in many areas of the United States that may not have had the necessary resources for sentinel lymph node biopsy, she continElizabeth Mittendorf, MD ued. “It will be interesting to see the data from 2007 to 2009, which will be available soon, to see if we have closed this gap,” she said.

Necessary Resources Nuclear physicists, tracers (colloid and blue dye), and the gamma probe are resources needed to perform sentinel lymph node biopsy. “I would like to think that these resources are now more widely available. I think the disparity in care may be driven more by geography and access to these resources than race. Most larger centers are now routinely performing [sentinel lymph node biopsy] in blacks and whites,” she stated. “My hypothesis is that hospitals in certain geographic areas were without the necessary resources during the period evaluated, but the disparity is probably due to a confluence of factors,” she speculated. “For me, the most interesting part of the study was the difference in rates of lymphedema between blacks and whites undergoing [axillary lymph node dissection]. We can’t tease out the contributing factors from the data that were presented. The extent of surgery is obviously a factor, but there are other factors as well. There is a need for genomic studies to identify factors that may be modifiable,” Dr. Mittendorf stated. n Disclosure: Dr. Mittendorf reported no potential conflicts of interest.

lymph node biopsy, rates of lymphedema were not significantly different according to race: 8.8% for black women and 6.8% for white women. The risk of lymphedema was in a similar range for blacks and whites who underwent sentinel lymph node biopsy, suggesting that when black patients are offered the appropriate surgery, they are not at greatly increased risk of lymphedema, Dr. Black said. Axillary lymph node dissection and black race were independent, significant predictors of risk of lymphedema (P < .001). Dr. Black and colleagues plan to study improve the accuracy as well as pathologic review of the sentinel nodes for treatment effect.” n

Disclosure: Dr. Boughey reported no potential conflicts of interest.

Reference 1. Boughey JC, Suman VJ, Mittendorf

the patterns of care from 2007 to 2009 to determine if access has improved for blacks. n

Disclosure: Dr. Black reported no potential conflicts of interest.

Reference 1. Black DM, Jiang J, Kuerer HM, et al: Disparities in the utilization of axillary sentinel lymph node biopsy among black and white patients with node negative breast cancer from 2002-2007. 2012 San Antonio Breast Cancer Symposium. Abstract S2-3. Presented December 5, 2012.

EA, et al: The role of sentinel lymph node surgery in patients presenting with node positive breast cancer (T0-T4, N1-2) who receive neoadjuvant chemotherapy: Results from the ACOSOG Z1071 trial. 2012 San Antonio Breast Cancer Symposium. Abstract S2-1. Presented December 5, 2012.

The ASCO Post | MARCH 15, 2013

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Journal Spotlight Breast Cancer

FOXP3 Expression Linked to Better Survival with Adjuvant Anthracycline Not Followed by Taxane in Breast Cancer By Matthew Stenger

he French UNICANCER-PACS 01 trial compared six cycles of anthracycline-based adjuvant therapy with FEC (epirubicin, cyclophosphamide, fluorouracil; FEC6) vs three cycles of FEC followed by three cycles of docetaxel (FEC/docetaxel) in patients with node-positive primary breast cancer. After adjuvant therapy, patients with hormone receptor–positive disease received endocrine therapy. Radiation therapy was recommended for all patients with conservative surgery and was performed at the investigator’s discretion after mastectomy. Patients with HER2-overexpressing disease did not receive trastuzumab (Herceptin) in the adjuvant setting. The trial showed that the addition of docetaxel reduced risk of relapse by 17%.1 A biomarker analysis of the trial, recently reported by Ladoire and colleagues in Annals of Oncology, indicates that overall survival was significantly improved in patients with tumors expressing FOXP3 compared with patients with FOXP3-negative tumors, among those who received the anthracycline-based adjuvant therapy without docetaxel.2 FOXP3, first identified as a transcription factor involved in the development and function of regulatory T cells, has been found in cancer cells and has been variously reported to be both a poor prognostic factor in breast cancer and a tumor-suppressor gene that acts as a transcriptional repressor of oncogenes such as HER2 and Skp2. In an earlier study, Ladoire and colleagues found that FOXP3 expression was predictive of improved survival in a small retrospective series of patients with breast cancer receiving neoadjuvant therapy, with data suggesting the difference in effect occurred in patients receiving anthracyclines but not in those receiving taxanes. Other recent studies indicated that FOXP3 expression might be associated with sensitivity to DNA-damaging agents and topoisomerase inhibitors.

Analysis of FOXP3 In the current analysis,2 the investigators found that 405 (36.9%) of 1,097 evaluable tumor samples from the PACS 01 study were FOXP3-pos-

itive. Tumor blocks were initially collected from 1,190 of the 1,999 patients in the trial. Clinical characteristics did not differ between patients tested for FOXP3 expression and those not tested, except for a greater frequency of T2 and T3 disease in the latter. Of the 1,097 evaluable patients, half had received FEC6 alone and half FEC/docetaxel. Among the 405 FOXP3-positive patients, 53.1% had received FEC/docetaxel; among the

cantly shorter for FOXP3-negative patients in the FEC6 group (P = .0005). Survival rates at 8 years were 83% in FOXP3-positive patients receiving FEC6 compared with 75% in FOXP3negative patients receiving FEC6, and 89% in FOXP3-positive patients receiving FEC/docetaxel compared with 86% in FOXP3-negative patients receiving FEC/docetaxel. On multivariate analysis, T stage, higher number of involved nodes, and

FOXP3, Anthracyclines, and Breast Cancer ■■ Among patients with breast cancer receiving anthracycline-based

adjuvant therapy without sequential taxane treatment, those with FOXP3expressing tumors had significantly better overall survival than patients with FOXP3-negative tumors.

■■ In vitro studies indicate that FOXP3 expression increases sensitivity of

breast cancer cells to anthracyclines and that FOXP3 expression can be induced in vivo by the HDAC inhibitor valproic acid.

692 FOXP3-negative patients, 48.4% had received FEC/docetaxel. Overall, 16% of patients had HER2-overexpressing tumors, including 14.1% of the FOXP3-positve group and 17.5% of the FOXP3-negative group. Patients with FOXP3-positive tumors were significantly more likely to have a lower tumor grade (I/II in 64.6% vs 50.5%, P < .001) and fewer involved nodes (1 to 3 in 67.2% vs 59.4%, P = .026), and were significantly less likely to have distant metastasis (19.5% vs 28%, P = .002) and to die (15.3% vs 22.5%, P = .004). The two groups did not differ with regard to HER2 status, treatment group distribution, T stage, hormone receptor status, locoregional relapse, or contralateral relapse.

high tumor grade remained independently associated with shorter survival. FOXP3-negative status also remained independently predictive of shorter survival, but only in the FEC6 arm (P = .011). Compared with this subgroup, risk of death was significantly reduced to a similar degree in the FOXP3-negative plus FEC/docetaxel (HR = 0.62, P = .008), FOXP3-positive plus FEC6 (HR = 0.62, P = .035), and FOXP3-positive plus FEC/docetaxel (HR = 0.57, P = .016) subgroups. The overall interaction between treatment and FOXP3 status was not significant (P = .4).

Survival Reduced in FOXP3negative Patients

To further assess the potential connection between FOXP3 expression and response to anthracyclines, the investigators performed studies to determine whether FOXP3 increased tumor cell sensitivity to anthracyclines in vitro. Prior studies had shown that HDAC inhibitors such as valproic acid can increase FOXP3 gene expression. The investigators found that FOXP3 expression was augmented in four of six breast cancer cell lines (HCC1954, MDA-MB-231, BT474, and HBL100, but not hs578T or MCF7) with low doses of valproic acid, with the induc-

On univariate analysis, factors associated with shorter survival were HER2 overexpression, high number of involved nodes, high tumor grade, hormone receptor–negative status, T stage, FEC6 treatment group, and FOXP3-negative status (hazard ratio =�� .003). Subgroup uni[HR] = 1.59, P �� variate analysis according to FOXP3 status and treatment arm showed that FOXP3 status was associated with shorter survival only in the FEC6 group—ie, overall survival was signifi-

FOXP3 Expression Increases Anthracycline Antitumor Activity

tion of FOXP3 being associated with downregulation of Skp2 protein. It was then found that valproic acid, which did not exert any antitumor activity alone, enhanced the cytotoxic effects of epirubicin in cell lines in which FOXP3 expression was increased and not in those in which no valproic acid–induced increase in FOXP3 expression was observed. Valproic acid treatment had no effect on the cytotoxic activity of docetaxel. In tumor cells (MDA-MB-231) knocked down for FOXP3 production (using small interfering RNA), valproic acid did not affect epirubicin activity, suggesting that the effect of valproic acid in increasing epirubicin activity was through enhanced FOXP3 expression. As noted by the investigators, their analyses suggests that absence of FOXP3 expression in breast tumors could identify a subset of patients with anthracycline-resistant disease who potentially derive marked benefit from the addition of a taxane to adjuvant therapy. The findings also emphasize the antioncogenic properties of the FOXP3 protein and recommend it as a target for future interventions in breast cancer. The investigators concluded, “[T] hese results strengthen the importance of the analysis of FOXP3 expression in patients with breast cancer, as such information can be used as an additional tool for the stratification of patients in clinical trials evaluating the benefits of taxanes or anthracyclines. It could also help clinicians for the selection of patients who would potentially derive the highest benefit from adding docetaxel in adjuvant chemotherapy and of patients who might benefit from additional therapies, like HDAC inhibitors, such as valproic acid, in future clinical trials.” n References 1. Roche H, Fumoleau P, Spielmann M, et al: Sequential adjuvant epirubicinbased and docetaxel chemotherapy for node-positive breast cancer patients: The FNCLCC PACS 01 trial. J Clin Oncol 24:5664-5671, 2006. 2. Ladoire S, Mignot G, Dalban C, et al: FOXP3 expression in cancer cells and anthracyclines efficacy in patients with primary breast cancer treated with adjuvant chemotherapy in the phase III UNICANCER-PACS 01 trial. Ann Oncol 23:25522561, 2012.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages. To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide

were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. ©2013 Celgene Corporation 02/13 US-POM120044a

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Inaugural Winners of $3 million Breakthrough Prize in Life Sciences Announced

rt Levinson, Sergey Brin, Anne Wojcicki, Mark Zuckerberg, Priscilla Chan, and Yuri Milner recently announced the launch of the Breakthrough Prize in Life Sciences, recognizing excellence in research aimed at

curing intractable diseases and extending human life. The prize will be administered by the Breakthrough Prize in Life Sciences Foundation, a not-forprofit corporation. The first 11 recipients of the Break-

through Prize, each of whom will receive $3 million for groundbreaking achievements in life science research are: Cornelia I. Bargmann, PhD, Torsten N. Wiesel Professor and Head of the Lulu and Anthony Wang Labora-

tory of Neural Circuits and Behavior at the Rockefeller University. Howard Hughes Medical Institute Investigator. For the genetics of neural circuits and behavior, and synaptic guidepost molecules. David Botstein, PhD, Director

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This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. 2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily. 500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma. Cosmos Communications

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of the Lewis-Sigler Institute for Integrative Genomics and the Anthony B. Evnin Professor of Genomics at Princeton University. For linkage mapping of Mendelian disease in humans using DNA polymorphisms. Lewis C. Cantley, PhD, Margaret and Herman Sokol Professor and Director of the Cancer Center at Weill Cornell

Medical College and New York-Presbyterian Hospital. For the discovery of PI 3-Kinase and its role in cancer metabolism. Hans Clevers, MD, PhD, Professor of Molecular Genetics at Hubrecht Institute. For describing the role of Wnt signaling in tissue stem cells and cancer. Napoleone Ferrara, MD, PhD, Distinguished Professor of Pathology and

Senior Deputy Director for Basic Sciences at Moores Cancer Center at the University of California, San Diego. For discoveries in mechanisms of angiogenesis that led to therapies for cancer and eye diseases. Titia de Lange, PhD, Leon Hess Professor, Head of the Laboratory of Cell Biology and Genetics, and Director of the Anderson Center for Cancer

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

(continued)

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

Cosmos Communications

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General disorders and administration site conditions

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

Research at the Rockefeller University. For research on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer. Eric S. Lander, PhD, President and Founding Director of the Eli and Edythe L. Broad Institute of Harvard and MIT. Professor of Biology at MIT. continued on page 76

The ASCO Post | MARCH 15, 2013

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News

Breakthrough Prize continued from page 75

Professor of Systems Biology at Harvard Medical School. For the discovery of general principles for identifying human disease genes, and enabling their application to medicine through the creation and analysis of genetic, physical and sequence maps of the human genome

Charles L. Sawyers, MD, Chair, Human Oncology and Pathogenesis Program at Memorial Sloan-Kettering Cancer Center. Howard Hughes Medical Institute Investigator. For cancer genes and targeted therapy. Bert Vogelstein, MD, Director of the Ludwig Center and Clayton Professor of Oncology and Pathology at

the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Howard Hughes Medical Institute Investigator. For cancer genomics and tumor suppressor genes. Robert A. Weinberg, PhD, Daniel K. Ludwig Professor for Cancer Research at MIT and Director of the MIT/Ludwig Center for Molecular

Oncology. Member, Whitehead Institute for Biomedical Research. For characterization of human cancer genes. Shinya Yamanaka, MD, PhD, Director of Center for iPS Cell Research and Application, Kyoto University, and Senior Investigator, Gladstone Institutes, San Francisco. For induced pluripotent stem cells. n

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Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

96 ( 90)

99 ( 88)

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations Pneumonia

17 ( 16)

26 (23)

Urinary tract infection

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders Hypercalcemia General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea

POMALYST + Low dose Dex (N=112)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders constipation

Blood and lymphatic system disorders Neutropenia

POMALYSTa (N = 107)

General disorders and administration site conditions

Cardiac Disorders

(continued)

Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and Cosmos Communications

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FDA Update

FDA Approves Regorafenib for Advanced Gastrointestinal Stromal Tumors

he FDA has expanded the approved use of regorafenib (Stivarga) to treat patients with metastatic or unresectable gastrointestinal stromal tumors (GIST) that no longer respond to treatment with ima-

tinib (Gleevec) or sunitinib (Sutent). Regorafenib, a multikinase inhibitor, blocks several enzymes that promote cancer growth. “[This] is the third drug approved by the FDA to treat gastrointesti-

nal stromal tumors,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It provides an important new treatment option for

patients with GIST in which other approved drugs are no longer effective.” Regorafenib was reviewed under the FDA’s priority review program,

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diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN.

which provides an expedited 6-month review for drugs that may provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products. The drug was also granted orphan product designation because it is intended to treat a rare disease.

Clinical Study

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

POMBS.001 02/13

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misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

The safety and effectiveness of regorafenib for this use were evaluated in a clinical study of 199 patients with unresectable GIST that had progressed after treatment with imatinib or sunitinib. Patients were randomly assigned to receive either regorafenib or a placebo. All patients received optimal supportive care. Patients in the study took regorafenib or placebo until disease progression or unacceptable toxicity. Results showed an average improvement of 3.9 months in patients who took regorafenib compared with patients who were given placebo. Patients who received the placebo were given the opportunity to switch to regorafenib when their cancer progressed.

Side Effects The most common side effects reported in patients treated with regorafenib were weakness and fatigue, palmar-plantar erythrodysesthesia, diarrhea, loss of appetite, high blood pressure, mouth sores, infection, changes in voice volume or quality, pain, weight loss, stomach pain, rash, fever, and nausea. Serious side effects, which occurred in less than 1% of patients, were liver damage, severe bleeding, blistering and peeling of skin, very high blood pressures requiring emergency treatment, heart attacks, and perforations in the intestines. Regorafenib was approved in September 2012 to treat colorectal cancer. It is marketed by Bayer HealthCare Pharmaceuticals. n Cosmos Communications

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Expert’s Corner Disaster Preparedness

Preparing for the Next Superstorm: Protecting Patients during Natural Disasters A Conversation with William L. Carroll, MD By Jo Cavallo

William L. Carroll, MD

hen Hurricane Sandy slammed into the East Coast last October, the magnitude of devastation it left in its wake exceeded even the most dire predictions. Eighty mile per hour winds and record storm surges destroyed antiquated electrical grids and flooded subway stations, leaving much of New York paralyzed and in the dark. The storm also caused NYU Langone Medical Center to shutter its doors and evacuate more than 300 critically ill patients, including two dozen patients with cancer, to area hospitals. Hundreds of other patients were discharged the weekend before the storm landed. The ASCO Post talked with William L. Carroll, MD, Director of the NYU Cancer Institute, and the Julie and Edward J. Minskoff Professor of Pediatrics and Professor of Pathology at NYU Langone Medical Center, about the damage to the hospital and its research laboratories, how the Medical Center is rebuilding to reduce the risk of such catastrophes in the future, and how to ensure that patients receive uninterrupted care when natural disasters strike.

Losing Power What caused the loss of your backup power generators, necessitating the evacuation of patients to local hospitals? We continue to assess the situation, but seven of our eight generators, which were situated above ground, were still functioning during the hurricane, so the generators did not fail. According to New York City building code, the fuel pumps supplying the generators have to be located in the basement, so the biggest culprit in

terms of the failure of the generators to supply power to the hospital was actually the fuel pumps, which were submerged in water. We were in the midst of a campus transformation project with the construction of a new energy building when Sandy hit us. That new energy building will have a self-generating energy unit so we will not be dependent on New York’s utility company, Con Edison, for power. The self-generating unit will be above ground, but Sandy hit before the building could be completed, which will be by 2015. But the campus was already moving in the direction of having an independent energy source before the storm landed.

Continuity of Care Where did the patients you evacuated go for treatment? When disasters like this strike you recognize the importance of having great colleagues. The bulk of our patients with cancer were cared for at Lenox Hill Hospital, where a designated floor was set up for our staff and patients, and Memorial Sloan-Kettering Cancer Center. The day after the hurricane hit, Dr. Craig Thompson [President and Chief Executive Office of Memorial Sloan-Kettering] called me, and we arranged for our patients to be cared for by Memorial’s oncologists in

Superstorm Sandy left the streets of Manhattan desolate.

cians visit them, even if it’s for a social call, because the doctor/patient relationship is crucial. And it works both ways: It was equally important to our doctors to stay in contact with their patients. Were you able to transfer patients’ electronic health records to the other institutions? No, we couldn’t transfer electronic records, but we did transfer summaries of each patient’s record and it worked out fine. Furthermore, the outside physicians caring for our patients had the cell phone numbers for each pa-

We are doing a lot on our campus to prevent this situation from ever happening again, so with each new building we construct, we are thinking about where we are putting the energy grid. —William L. Carroll, MD

concert with our oncologists. Our pediatric patients with cancer were taken to Mount Sinai Medical Center, and other area hospitals cared for the rest of the patients. All our patients had continued care by NYU doctors. Even though we didn’t have hospital privileges in all circumstances, our patients could still see us on a daily basis, and I think that was critical to their care. So if patients have to be transferred to other venues, my advice is to make sure that their physi-

tient’s primary NYU oncologist to ensure seamless communication and continuity of care.

Further Precautions Are there additional steps hospitals can take to ensure that treatment remains uninterrupted during natural disasters like Hurricane Sandy? We had an evacuation plan in place at the time Sandy struck, and we put together a relationship with area hospitals very quickly to allow patient care

to continue uninterrupted. Communication was greatly hampered throughout much of New York. Internet and phone services were down, and that was a real problem for us, because it was really hard to get information to our patients. We set up an 800 number with an independent network to be able to maintain continued communication with our patients for the 5 days before electrical power was restored throughout the city. So you need to have that emergency number ready to be operational. I already had phone numbers for all senior staff programmed into my cell phone, and texting worked when regular service was unavailable. Although many of our inpatients needed to be temporarily treated elsewhere, our outpatient cancer center was able to reopen the Monday following the storm. When we knew that the outpatient cancer center was going to be closed, we were able to make contact with patients through an automated call system. Once we knew power was restored to the Midtown area, we made a concerted effort to make personal calls to reschedule patients who missed their appointments. Hours of operation were extended as well to accommodate the additional volume. From a telecommunications perspective, the ability to contact our patients was sometimes challenging. I’m a pediatric oncologist, and the second day after the storm, the mother of one of my young patients walked all

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Expert’s Corner

the way from Chinatown to the medical center—about 3 miles—with her 2½-year-old child, and I just happened to meet her there. It was very emotional to meet up with my patient in those circumstances and to know that things were still all right, reinforcing how critical communication is during a disaster like this.

Getting the Word Out How were you able to announce the 800 number to your patients? In addition to working with local and national media to inform our patients of the status of the medical center, we also used other venues such as social media for patients who were able to access the Internet. We posted information on NYU’s Facebook page and kept patients informed that way, so I would also highly recommend using social media to get the word out. Our medical center website home page was updated on a regular basis as well.

Calculating the Losses How severe was the flood damage to your basement research laboratories? Estimates of the destruction are between $50 million and $100 mil-

lion, but we are still evaluating the loss. Importantly, we did not lose clinical samples housed in our biobank. We place a high priority on clinical samples because that is a legacy for future generations, and those were protected in tanks of liquid nitrogen and/or housed in separate areas in anticipation of something like this happening. Of course, reagents and peoples’ time (when it comes to conducting experiments) were lost, and we are still determining how to calculate those losses.

Research Setbacks How much time was lost in advancing the center’s research? I think the majority of researchers had their work set back between 3 and 5 months. For those who lost laboratory animals, there was a more severe setback. One research building still had emergency power, and we were able to transfer reagents to that building. A lot of this work was done by hand through the heroics of post-docs and graduate students who carried samples to the building. But we did lose reagents, and the severity varies among investigators. We were able to reopen our inpatient hospital on January 14, and many of the

Damages to Medical Center Estimated at $1 Billion

YU Langone Medical Center, which stretches across four blocks on Manhattan’s East Side and comprises four hospitals, a medical school, and an outpatient cancer institute, sustained an estimated $1 billion in damages to its main inpatient campus, which is located one block from the East River. Fifteen million gallons of sea water rushed into the basement and subbasement of the hospital, which housed four magnetic resonance scanners, a linear accelerator, and gamma knife surgery equipment, as well as research laboratories, submerging them in over 14 feet of salt water. The National Institutes of Health puts the loss in research experiments and destruction to laboratory equipment and animals at between $50 million and $100 million. n

research labs came back well before then. So while the storm caused a major blow, we are now up and fully operational, and our research is continuing.

Closing Thoughts What advice do you have for ASCO members on how to protect their patients with cancer in similar circumstances? An evacuation plan and a plan for providing alternatives for continued care are important. We are doing a lot on our campus to prevent this situation from ever happening again, so with

each new building we construct, we are thinking about where we are putting the energy grid, which is why our new energy building is so important. I think every hospital has to consider a similar solution. Should power go down, even with emergency generators, how long will that power last? Having an independent, self-generating source of energy is key. Having a plan in place to be able to maintain communication with patients is also crucial. n

Disclosure: Dr. Carroll reported no potential conflicts of interest.

High Infection Rates Found in Multiple Myeloma Patients, With High Mortality By Jo Cavallo

large Swedish study using population-based data to estimate the risk of bacterial and viral infections among 9,610 patients with multiple myeloma (9,253 eligible for analysis) found that the myeloma patients had a 7-fold risk of developing any infection compared to 34,931 matched controls from the Swedish Population Database (hazard ratio [HR] = 7.1; 95% confidence interval [CI] = 6.8–7.4). The increased risk of developing a bacterial infection was 7-fold (HR = 7.1; 95% CI = 6.8–7.4), and for viral infections, 10fold (HR = 10.0; 95% CI = 8.9–11.4). The risk of specific infections, such as pneumonia and septicemia, was over 10 times higher in myeloma patients than in the controls during the first

year of diagnosis. The research was presented at the 54th Annual Meeting of the American Society of Hematology (ASH) in Atlanta.1 The risk of infections was highest during the first year after diagnosis. The risk of bacterial infections was 11-fold,

fold; from 1994 to 1999, the risk was 7-fold; and from 2000 to 2004, the risk was 8.9-fold compared to controls. Women had a significantly lower risk of developing infections compared to men (P < .001). Increasing age was significantly associated with a higher

The effect of novel drugs on infectious complications in the treatment of multiple myeloma needs to be established. Regardless of the cause, clinical trials of prophylactic measures are needed. —Cecilie Bilmark, MD

and the risk of viral infections was nearly 18-fold. The risk of infections in multiple myeloma patients increased significantly with time compared to controls. From 1988 and 1993, the risk was 5.7-

risk of infections (P < .001). At both 2 months and 1 year after diagnosis, 22% of the multiple myeloma deaths were infection-related. The exact reason why there has

been a rise in infection risk is unclear, Cecilie Bilmark, MD, a hematologist at Sahlgrenska University Hospital in Gothenburg, Sweden, and lead author of the study told conference attendees. However, she commented, the effect of novel drugs on infectious complications in the treatment of multiple myeloma needs to be established. Regardless of the cause, said Dr. Bilmark, clinical trials of prophylactic measures are needed. n Disclosure: Dr. Bilmark reported no potential conflicts of interest.

Reference 1. Bilimark C, Mellqvist UH, Landgren O, et al: Multiple myeloma and infections: A population-based study based on 9,610 multiple myeloma patients. 2012 ASH Annual Meeting. Abstract 945. Presented December 11, 2012.

NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated

with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

I N T R O D U C I N G More than 20,000 patients with mCRPC have received ZYTIGA® (post-chemotherapy with docetaxel) to date.†1

MECHANISM OF ACTION ZYTIGA® is a CYP17 (17 -hydroxylase/C17, 20-lyase) inhibitor that inhibits androgen production at 3 sources: the testes, adrenal glands, and the prostate tumor tissue itself.

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.* Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy containing docetaxel.*

ZytigaOne™ is your single source for personalized access services for you and your patients: Visit www.zytigaone.com or call 1-855-998-4421. *Study Designs: ZYTIGA®, in combination with prednisone, was evaluated in 2 Phase 3, randomized, double-blind, placebo-controlled, multicenter trials in patients with mCRPC. Study 1 enrolled patients who received prior chemotherapy containing docetaxel (N = 1,195), whereas Study 2 enrolled patients who had not received prior chemotherapy (N = 1,088). In both studies, patients were using a luteinizing hormone-releasing hormone agonist or were previously treated with orchiectomy. In the active treatment arms, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the control arms, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In Study 1, the primary efficacy endpoint was overall survival. In Study 2, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. † Estimate based on sales and use data from May 2011 to November 2012. Reference: 1. Data on file. Janssen Biotech, Inc.

www.zytigahcp.com Please see adjacent pages for brief summary of full Prescribing Information.

K08Z121176

Adverse Reactions—The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 12/12 08Z12264B

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castrationresistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot ﬂush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) Grade 3-4 All Grades1 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

7.6

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse

events graded according to CTCAE version 3.0 terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial ﬁbrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial ﬂutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 2 Includes 3 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Laboratory Abnormality Hypertriglyceridemia High AST Hypokalemia Hypophosphatemia High ALT High Total Bilirubin

Abiraterone (N=791) All Grades Grade 3-4 (%) (%) 62.5 0.4 30.6 2.1 28.3 5.3 23.8 7.2 11.1 1.4 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Prednisone (N=542) Grade 3-4 System/Organ Class All Grades1 Adverse reaction % % General disorders Fatigue 39.1 2.2 Edema2 25.1 0.4 Pyrexia 8.7 0.6 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 Groin pain 6.6 0.4 Gastrointestinal disorders Constipation 23.1 0.4 Diarrhea 21.6 0.9 Dyspepsia 11.1 0.0 Vascular disorders Hot ﬂush 22.3 0.2 Hypertension 21.6 3.9 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 Dyspnea 11.8 2.4 Psychiatric disorders Insomnia 13.5 0.2 Injury, poisoning and procedural complications Contusion 13.3 0.0 Falls 5.9 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 Nasopharyngitis 10.7 0.0 Renal and urinary disorders Hematuria 10.3 1.3 Skin and subcutaneous tissue disorders Rash 8.1 0.0 1 Adverse

events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Placebo with Prednisone (N=540) All Grades Grade 3-4 % % 34.3 20.7 5.9

1.7 1.1 0.2

25.2 4.1

2.0 0.7

19.1 17.8 5.0

0.6 0.9 0.2

18.1 13.1

0.0 3.0

13.5 9.6

0.2 0.9

11.3

0.0

9.1 3.3

0.0 0.0

8.0 8.1

0.0 0.0

5.6

0.6

3.7

0.0

ZYTIGA® (abiraterone acetate) Tablets

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Storage and Handling: Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 30oC (59oF to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Speciﬁc Populations].

Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Laboratory Abnormality Hematology Lymphopenia Chemistry Hyperglycemia1 High ALT High AST Hypernatremia Hypokalemia 1Based

Abiraterone (N = 542) Grade 1-4 Grade 3-4 % %

Placebo (N = 540) Grade 1-4 Grade 3-4 % %

38.2

8.7

31.7

7.4

56.6 41.9 37.3 32.8 17.2

6.5 6.1 3.1 0.4 2.8

50.9 29.1 28.7 25.0 10.2

5.2 0.7 1.1 0.2 1.7

on non-fasting blood draws

Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information]. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: December 2012 2000005445 K08Z121174A

The ASCO Post | MARCH 15, 2013

PAGE 84

Journal Spotlight Health Information Technology

Enhanced Electronic Module Aims to Prevent Errors in Oral Chemotherapy Prescribing By Charlotte Bath

n oral chemotherapy prescription-writing module grafted to a shared electronic medical record is part of a series of quality improvement efforts undertaken at DanaFarber Cancer Institute in Boston to prevent errors in prescribing oral chemotherapy agents. While oncologists have readily accepted the module, modifications are planned to make it easier to prescribe drugs with complex dosing regimens and ensure that dose-limit warnings reflect current clinical practice, according to an article published in the Journal of Oncology Practice ( JOP).1 The prescription-writing module builds on findings from previous ef-

forts to identify and address key vulnerabilities associated with the use of oral chemotherapy agents2 and uses some of those findings to enhance the longitudinal medical record. The longitudinal medical record is described in the JOP article as “a multifeature electronic medical record shared with clinicians across the affiliated Partners Healthcare system, to document encounters, check laboratory and diagnostic test results, and generate prescriptions that can be printed, faxed, or transmitted electronically to pharmacies.” The Partners Healthcare system includes Dana-Farber, as well as Brigham and Women’s Hospital and Massachu-

setts General Hospital in Boston and affiliated community hospitals and practices in eastern Massachusetts and New Hampshire. New features added to the existing system made it more specific for oral chemotherapy drugs. “With guidance from physician, nurse, pharmacy, and information technology colleagues, we designed several safety-oriented enhancements to the existing module to support safe prescribing of oral chemotherapy. The enhancements included the ability to order oral chemotherapy based on a fixed dose, a weight-based dose, or a dose based on body surface area,” the authors explained. The en-

Medication Safety at Home

risk assessment to identify how errors occur when oral chemotherapies are used by pediatric patients at home (and to propose riskreduction strategies) relied on input from those primarily in charge of oral chemotherapy use at home—the parents. A total of 18 parents were recruited at three pediatric oncology clinics in high- and low-volume clinics in the northeast and southeast United States. “Parents identified 69 failure modes that could occur in the process of home use of oral chemotherapy after a change in medication dose,” investigators reported in the Journal of Oncology Practice.1 The highest-ranked factor was “misunderstanding physician instructions about changes in medication doses, either through misunderstanding on the part of the parent or conflicting instructions being received from different clinicians,” the authors stated. “The second was the unsafe handling of chemotherapy medications at home,” and the third was “the child refusing to take the medication or vomiting the medication for several days.”

Recommended Strategies Strategies recommended by parents to reduce risks at home “fell into three general categories,” according to the researchers, who listed them as follows: 1. Streamline current processes (eg, issue updated home medication

list, have one designated point of clinical contact, bring home caregivers in for doctor visits) 2. Offer additional information/ support from clinicians (eg, print or e-mail after-visit summaries, provide virtual help/support via e-mail or Web portal, have a nurse make one or multiple home visits, recommend when to call the doctor about home medication use, provide standard form for parents to take notes during doctor visits, prepare a medication calendar with check boxes) 3. Supply additional information/ support via parents (eg, parent-run listserve/chat room or “parent-run WebMD”)

New ASCO/ONS Standards Expected Parents and other family members are “often unaware” about safe handling practices and “surprised when they hear that there are some issues around that,” Saul N. Weingart, MD, PhD, one of the article’s authors, told The ASCO Post. Dr. Weingart is Vice President for Quality Improvement and Patient Safety at Dana-Farber Cancer Institute, Boston. “Certain oral chemotherapy drugs should not be handled with bare hands; people should be gloved. If you are going to be cutting the pills or pouring liquid, how are you going to make sure the surfaces you cut the pills on,

the knife, and the cup are clean and then sanitized afterwards, so that other children are not exposed to the drug?” These issues are part of increasing attention to providing education for patients and families about how to use these drugs safely, Dr. Weingart said. “Oral chemotherapy is getting to be a very, very hot topic, and the American Society of Clinical Oncology (ASCO) and Oncology Nursing Society (ONS) are going to be coming out with recommendations regarding standards for prescribing and administering oral chemotherapy.” The new ASCO/ONS standards are expected to include guidelines that support safe adherence at home, safe handling practices, monitoring, and other types of patient care “that occurs outside of the normal control of the cancer center.” Dr. Weingart said. “When the ASCO/ONS standards come out, a lot of cancer centers and practices around the country are going to be looking at what they do and thinking about where there are opportunities for improvement.” n

Disclosure: Dr. Weingart and coauthors reported no potential conflicts of interest.

Reference 1. Walsh KE, Mazor KM, Roblin D, et al: Multisite parent-centered risk assessment to reduce pediatric oral chemotherapy errors. J Oncol Pract 9:e1-e7, 2013.

Saul N. Weingart, MD, PhD

hanced system provided a calculator to support toxicity-related dose adjustments.

A Welcomed Enhancement, Though Work in Progress An analysis of all prescriptions for chemotherapy agents during the first 17 months after the module was introduced showed that “clinicians used the enhanced oral chemotherapy prescription module extensively. Oncologists accepted the changes without resistance or complaint,” said the authors. “Many saw [the new module] as an enhancement,” Saul N. Weingart, MD, PhD, Vice President for Quality Improvement and Patient Safety at Dana-Farber Cancer Institute, said in an interview with The ASCO Post. Dr. Weingart is also lead author of the JOP article. “We sent out some notification in advance that it was coming and people just used it. Clinicians are used to electronic prescribing, and we just added some bells and whistles for them to take advantage of. I think some of the changes were welcome,” Dr. Weingart said. During the analysis period, “600 oncology prescribers entered 6,673 prescriptions into the electronic medical record for 18 different oral chemotherapies,” according to the analysis. Six drugs accounted for 83% of the total prescriptions—temozolomide, capecitabine (Xeloda), lenalidomide (Revlimid), hydroxyurea, imatinib (Gleevec), and erlotinib (Tarceva). “The enhanced oral chemotherapy prescribing module offered clinicians the opportunity to specify the intent of therapy (curative or palliative) and display the diagnosis, replicating safety features required for infusion therapy,” the article’s authors reported. These optional fields on the prescribing module were used inconsistently. Intent of therapy was specified 13% of the time,

ASCOPost.com | MARCH 15, 2013

PAGE 85

Journal Spotlight

and cancer diagnosis, 46% of the time. A free-text field allowed prescribers to customize their prescriptions, adding information about treatment dates, dose calculations, whether patients should take medications with food, and the number of tablets of different strength that should be taken together. This field was used in 4,242 (63.6%) of 6,673 prescriptions. The investigators concluded that modifications are needed to make it easy for prescribers to incorporate information currently provided in freetext fields. “Offering a streamlined way to include this information in the prescription may permit quicker prescription writing, facilitate complete prescriptions, and offer more comprehensive data capture,” they stated.

rather than being an interruption or a distraction. Other studies have shown that “in general ambulatory care, the override rate of alerts is about 90% in most settings,” Dr. Weingart added. “Overridden alerts don’t necessarily mean the alerts were not useful,” he continued. “Sometimes the physician will decide to proceed with the

prescription despite an alert because it has reminded him or her to monitor a lab parameter or to bring the patient in a little more quickly. But some of the alerts are really not appropriate, and we need to be careful about providing decision support that really doesn’t support decisions, that actually is outdated, inaccurate, or inap-

propriate.” Dr. Weingart said that he was a bit dismayed that no one notified him or others in his department about the outdated dose limit alerts. “We heard nothing about it,” he said, discovering the problem only during the analysis. He speculated that maybe clinicians “are continued on page 86

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

ANOTHER SIDE OF RCC

‘Inappropriate Alerts’ As with other prescriptions in the system, “oral chemotherapies could generate drug allergy and interaction alerts and trigger geriatric and renal dose warnings,” Dr. Weingart and colleagues explained. “We enhanced these decision support tools by creating, with the assistance of oncologists and oncology pharmacists, daily and weekly dose-limit warnings that would alert the prescriber to potential overdoses.” During the first 17 months only, dose-limit warnings were generated. Prescriptions for seven drugs generated all 395 alerts (Table 1, page 86). Temozolomide alone accounted for 374 alerts (95%). “A clinician whose prescription generated an alert had the option of aborting the prescription attempt or completing the prescription as planned,” the JOP article noted. Clinicians ignored most (96%) of these alerts. Only 17 (4%) of the 395 prescriptions that generated an alert were aborted (Table 2, page 86). “In retrospect, it is surprising that clinicians aborted any prescriptions. Current dosing recommendations exceeded the dose-limit warnings for the alerted medications in every case, thus generating a significant number of inappropriate alerts,” the authors noted. “When we created the alerts, they were based on current published guidelines, but by the time the system was implemented, practice had evolved so quickly that the dose limits were out of date,” Dr. Weingart explained. “If we are providing alerts to providers, we should make sure that they are helpful,

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown. 2 The American Cancer Society estimates that there will be 64,770 new cases of RCC and 13,570 RCCrelated deaths in 2012. 3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations. 5,8,9 In the Phase 3 trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.7 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living. 5,8

Is good enough, enough? Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical. 3 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.4,5

Furthermore, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy. 8 Other factors that may affect adherence include misinterpretation of physician instructions, polypharmacy syndrome and lifestyle distractions (e.g., demands of work and family, lack of support).10

Therapy for advanced RCC has evolved…

There may be opportunities to improve patient care

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.6

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to try to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives. 5,8

Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.7,8

Go behind the scenes to learn more at www.AnotherSideOfRCC.com.

AVEO and Astellas are uncompromising in their commitment to RCC References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012. 4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30. 6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin North Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y. 10. Moore S. Cancer Nurs. 2007;30:112-122.

An Uncompromising Commitment to RCC

012I-073-6291

09/12

Printed in USA

The ASCO Post | MARCH 15, 2013

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Journal Spotlight

Oral Chemotherapy Errors continued from page 85

just used to getting unhelpful alerts in a variety of systems.” The analysis showed that “we needed to circle back and make sure” that the dose-limit alerts were based on “real-time clinical input,” Dr. Weingart said.

No Drug Interaction Alerts Although the enhanced system “could flag interactions between the oral chemotherapy medicines and any of the other medicines that are on the patient’s medication list,” Dr. Weingart said, “there wasn’t a single alert that was generated about an interaction between an oral chemotherapy agent and one of the patient’s other drugs. The alert rate in ambulatory care is around 2% to 3%, so with 6,000 prescriptions, you would expect there would be a bunch of drug interaction or drug allergy alerts that would pop up, but they didn’t. It is really quite odd. I think the most likely reason is that we haven’t discovered a lot of interactions between oral chemotherapies and other drugs.” The lack of interactions “raises this question about whether our electronic decision support is built in a way that picks up those interactions. It is possible that there really aren’t many, or it is possible that the vendors creating these alerts just haven’t built that section out yet,” he continued. “We have started to look at alerts generated in the chemotherapy infusion order-entry system for interactions with drugs in the patient’s ambulatory medical record, including oral chemotherapies. Those alerts often do change physician behavior,” Dr. Weingart said. Drugs that can have interactions with infusional chemotherapy agents include blood pressure medicines, choles-

terol medicines, seizure medicines, and antidepressants, Dr. Weingart noted.

Table 1: Oral Chemotherapy Alerts by Type of Alert and Drug Namea

Other Medication Safety Updates Hormonal chemotherapies and investigational agents are not included in the enhanced oral chemotherapy prescription module, but Dr. Weingart said he expects that investigational agents will be added in the near future. “It is complicated because we have over 600 trials in place, and each drug needs to be coded separately.” Dr. Weingart noted. “There still is no enthusiasm for incorporating hormonal therapy into this system. The thought is that there is less danger in their use, and safety features aren’t as important for this relatively benign intervention,” he added. “The other thing that we are going to be rolling out shortly is an alert that reminds the provider to complete or update an informed consent form for oral chemotherapy. One of the best practice recommendations is that patients complete a written informed consent for oral agents in just the way they do for infusion therapy. There is some inconsistency in practice across the country, so we are trying to build in a feature that ensures clinicians get written informed consent consistently.” n

Alert

Number of Alerts

Number of Prescriptionsb

Alerts per 100 Prescriptionsb

Dose-limit warning

395

6,673

5.9

Capecitabine

1,168

0.9

Dasatinib

1.3

Erlotinib

349

0.6

Hydroxyurea

657

0.9

Mercaptopurine

151

0.7

Methotrexate

145

0.7

Temozolomide

374

1,585

23.6

Drug generating alert

Table 2: Prescriber Actions in Response to Oral Chemotherapy Alerts by Drug and Type of Prescribera Prescriber Action after Alert Drug/Prescriber

Abort Prescription

Continue Prescription

Continuation Rate

Drug generating alert

P Valueb < .001

Capecitabine

80%

Dasatinib

Erlotinib

100%

Hydroxyurea

100%

Disclosure: Dr. Weingart and coauthors reported no potential conflicts of interest.

Mercaptopurine

100%

Methotrexate

100%

References 1. Weingart SN, Mattsson T, Zhu J, et al: Improving electronic oral chemotherapy prescription: Can we build a safer system? J Oncol Pract 8(6):e168-e173, 2012. 2. Weingart SN, Spencer J, Buia S, et al: Medication safety of five oral chemotherapies: A proactive risk assessment. J Oncol Pract 7(1):2-6, 2011.

Temozolomide

360

96%

Type of Prescriber

.07

Physician

139

93%

Nonphysician

239

97%

Download The ASCO Post iPad App FREE from iTunes today!

ASCOPost.com | MARCH 15, 2013

PAGE 87

Journal Spotlight Gynecologic Oncology

Analysis Shows No 10-year Survival Advantage in Patients with Ovarian Cancer and BRCA1 or BRCA2 Mutations By Matthew Stenger

everal studies have suggested that short-term overall survival for women with ovarian cancer and BRCA1 or BRCA2 mutations is better than that in patients without such mutations. Indeed, a recent report by Kelly L. Bolton, PhD, and colleagues indicated that 5-year overall survival was 36% for mutation noncarriers, 44% for BRCA1 carriers, and 52% for BRCA2 carriers.1 However, a more recent analysis by John R. McLaughlin, PhD, and colleagues reported in the Journal of the National Cancer Institute indicates that although patients with such mutations have significantly reduced risk of death from cancer at 3 years, there is no difference between mutation carriers and noncarriers at 10 years.2 The analysis included 1,626 unselected women diagnosed with invasive ovarian cancer between 1995 and 2004 in Ontario, Canada, or Tampa, Florida, for whom mutation status could be ascertained. Mutation screening showed BRCA1 (n = 129) or BRCA2 (n = 89) mutations in 218 women (13.4%). Age at diagnosis was 51 years in BRCA1 carriers, 58 years in BRCA2 carriers, and 58 years in noncarriers. Eighty-five percent of BRCA1 carriers, 76% of BRCA2 carriers, and 88% of noncarriers were from Ontario. Patients were followed for a mean of 6.9 years.

Baseline Characteristics There were marked imbalances in disease characteristics between mutation carriers and noncarriers at baseline, including worse stage, grade, and histology among carriers. Stage III or IV tumors were present at baseline in 81% of carriers (74% with BRCA1 mutation and 84% with BRCA2 mutation) vs 63% of noncarriers (P < .0001). Grade 1 disease was present in 15% of noncarriers vs 2% of BRCA1 mutation and 0% of BRCA2 mutation carriers, whereas grade 3 disease was present in 32% of noncarriers vs 57% of BRCA1 mutation and 53% of BRCA2 mutation carriers. Serous histology was present in 53% of noncarriers vs 74% and 73% of carriers (overall 53% vs 73%, P < .01). On crude survival analysis, despite the baseline imbalances, muta-

tion carriers had better 3-year survival than noncarriers, including improved survival among patients with stage III or IV tumors, although no difference between groups was apparent at 10 years. Among patients with serous cancer, which was associated with the greatest mortality, there was no difference in survival between mutation carriers and noncarriers at 10 years.

Annual Mortality Analysis of ovarian cancer mortality in yearly intervals showed that annual mortality was lower among carriers for years 1 and 2 after diagnosis but similar or higher thereafter. Among 309 women who survived for 12 years, only 1 death from ovarian cancer occurred thereafter in 588 person-years of observation, suggesting that 12year survival is a reasonable surrogate for cure. At 12 years after diagnosis, 29.5% of BRCA1 mutation carriers, 27.7% of BRCA2 mutation carriers, and 41.2% of noncarriers were alive,

fidence interval [CI] = 0.63–1.01, P = .06). At 10 years, there was no difference in ovarian cancer mortality between groups (HR = 1.00, 95% CI = 0.83–1.22, P = .90). Among women with stage III disease, adjusted hazard ratios for ovarian cancer death for carriers vs noncarriers were 0.60 (P = .07) at 3 years, 0.73 (P = .08) at 5 years, and 0.95 (P = .70) at 10 years. Among women with serous ovarian cancer, carriers had a significantly reduced risk of death on adjusted analysis at 5 years (HR = 0.75, P = .04) but not at 10 years (HR = 0.92, P = .49).

Study Limitations There are several potential drawbacks in the analysis. Blood samples for mutation screening were obtained from only a minority of eligible cases. In Toronto, for example, blood samples were obtained from 42% of 3,367 eligible cases. More than 1,000 patients who died before samples could be obtained were not included in the

BRCA Mutations and Survival in Ovarian Cancer ■■ Mortality from ovarian cancer was lower among BRCA1 or BRCA2 mutation carriers than among noncarriers at 3 years but not at 10 years.

■■ Mutation carriers had peak mortality later after diagnosis than noncarriers

(3.5 vs 2 years), suggesting that 5-year survival may not provide an accurate picture of relative longer-term survival in carriers and noncarriers.

■■ Findings in this analysis indicate that survival at 12 years after diagnosis

was a reasonable surrogate for cure. Among patients with serous ovarian cancer, 27.4% of BRCA1 carriers, 27.7% of BRCA2 carriers, and 27.1% of noncarriers were alive at 12 years.

including 27.4%, 27.7%, and 27.1% of those with serous ovarian cancer, and 39.2%, 35.0%, and 40.8% of those with stage III disease at diagnosis. To address the baseline imbalances in disease severity, a multivariable analysis was performed to adjust for histology, age at diagnosis, disease stage, and disease grade. On the adjusted analysis, mortality from ovarian cancer was significantly lower at 3 years among carriers vs noncarriers, with carriers having a 32% reduction in risk of death (adjusted hazard ratio [HR] = 0.68, P = .03). At 5 years, there was a 21% reduction in risk of death in carriers that approached significance (HR = 0.79, 95% con-

analysis, thus biasing the analysis in favor of survivors; the analysis included a statistical method (left-truncated survival analysis) meant to adjust for the fact that patients dying shortly after diagnosis often could not have mutations status ascertained. In addition, many patients or their physicians declined to participate in testing and many patients could not be located. Participation may thus have differed by age, ethnicity, or other factors. Finally, no data on treatment were included in the model used in the analysis; the authors note, however, that treatment regimens were relatively standard across North America and treating physicians were

unaware of the mutation status of the study patients.

Different Survival Patterns As noted by the authors, the finding of an early survival advantage in mutation carriers followed by higher mortality rates suggests that hereditary and nonhereditary case patients have distinct survival patterns. Available data suggest that the differences between carriers and noncarriers in this regard are not due to difference in intrinsic aggressiveness of the cancers, but rather due to better initial response to chemotherapy in carriers; in this regard, a number of studies have showed better responses to chemotherapy in BRCA1 or BRCA2 carriers. In the current analysis, peak mortality occurred at 2 years after diagnosis in noncarriers and at 3.5 years after diagnosis in carriers, raising the issue of whether hazard ratios calculated at 5 years after diagnosis are likely to give an accurate picture of long-term survival differences among mutation carriers and noncarriers. The investigators concluded: “Our data indicate that the short-term survival benefit of carrying a BRCA1 or BRCA2 mutation is not reflected in long-term differences in the proportions of women who ultimately survive their ovarian cancer. We believe that there is insufficient evidence to conclude that survival from ovarian cancer differs between carriers and noncarriers, and we disagree with [any recommendations] that health-care providers should counsel women with ovarian cancer and carrying BRCA mutations that they should expect their survival to be better than that of noncarriers or that treatment could be tailored to reflect the difference in survival.” n Disclosure: The study authors reported no potential conflicts of interest.

References 1. Bolton KL, Chenevix-Trench G, Goh C, et al: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA 307:382-390, 2012. 2. McLaughlin JR, Rosen B, Moody J, et al: Long-term ovarian cancer survival associated with mutation in BRCA1 or BRCA2. J Natl Cancer Inst 105:141-148, 2013.

The ASCO Post | MARCH 15, 2013

PAGE 88

Announcements

Research Leader Helen Piwnica-Worms, PhD, Appointed Vice Provost, Science, at UT MD Anderson Cancer Center

elen Piwnica-Worms, PhD, a leader and scientist whose success in cancer research spans the spectrum from basic science discovery through arduous preclinical follow-up and delivery of potential new drugs to clinical trial, will lead science research at The University of Texas MD Anderson Cancer Center, Houston, starting June 1. She will serve as Vice Provost, Science, overseeing preclinical and basic science research. She also will be a Professor in MD Anderson’s Department of Cancer Biology.

an instrumental role in building the Molecular Oncology program and establishing the Siteman Cancer Center.

J9042

Important Safety Information

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Innovative Investigations “Helen’s career has been marked by continual waves of innovation and translation. Her pioneering work in cell-cycle checkpoints has been translated into new therapeutic opportunities for cancer patients,” said MD Anderson President Ronald A. DePinho, MD. “Her powerful blend of great science and effective translation, coupled with her strategic bandwidth, make her uniquely qualified to guide our laboratory sciences into an exciting era of vibrant discovery and clinical impact,” he added.

Leadership Success During her 19 years at Washington University, Dr. Piwnica-Worms became a Howard Hughes Medical Institute investigator and assumed greater levels of leadership, playing

CD30-directed therapy

effective 1/1/13

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS® (brentuximab vedotin).

Dr. Piwinca-Worms is currently Head of the Washington University School of Medicine Department of Cell Biology and Physiology as well as Associate Director for Basic Science and Executive Committee Member at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis.

son to lead the Department of Cancer System Imaging and as Deputy Division Head, Research, in the Division of Diagnostic Imaging. n

Announcing: J-code

BOXED WARNING

Helen Piwnica-Worms, PhD

She also collaborates with her spouse, David Piwnica-Worms, MD, PhD, in molecular imaging research. He is coming to MD Ander-

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

CT SCANS confirmed responses in relapsed patients Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9 120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/ Lin:DCM/id:ID W:200 L25

ASCOPost.com | MARCH 15, 2013

PAGE 89

Announcements

City of Hope Names Robert Stone, JD, as New Chief Executive Officer

fter 10 years at City of Hope, in Duarte, California, former FDA acting Commissioner Michael A. Friedman, MD, has decided to retire from his position as Chief Executive Officer, and the Board of Directors

has selected current President Robert Stone, JD, to assume the dual role of President and Chief Executive. The change will continue the momentum of the $1.1billion independent biomedical research, treatment, and ed-

ucation institution. “Dr. Friedman has served City of Hope during a period of remarkable growth over the last 10 years. Now, as he prepares to retire as planned— and as we look ahead to the future—

After multiple failures,

single-agent response Indicated for the treatment of:

Important Safety Information (continued)

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

sALCL: 86% ORR (95% CI: 77%-95%)

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS® (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

2011 August 19 Acq Tm: 14:05:52

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

512x512 B

A R

• P rogressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS® (brentuximab vedotin)– treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with newonset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • U se in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

L Vp

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad. REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012. US/BVP/2011/0104i

855.4SEAGEN (855.473.2436) SeaGenSecure.com

we are convinced that Robert Stone is the right person to take this new leadership role,” said board Chair Sheri Biller. “Having been instrumental in strategically positioning continued on page 90

The ASCO Post | MARCH 15, 2013

PAGE 90

Announcements

Robert Stone, JD continued from page 89

City of Hope as a scientific and medical institution of national renown, Robert has the experience and the vision to advance our commitment to science in the service of health, build on the incredibly strong foundation already in place, and direct

City of Hope toward further growth amid the dramatic changes in health care.”

Coordinated Transition The change will officially take place at the end of 2013. Until then, Mr. Stone will work closely with Dr. Friedman—with whom the board consult-

ed about the appointment—to ensure a smooth, coordinated transition. He will also be working closely with a strong executive-level team, many of whom were brought onboard in the past few years to ensure a solid foundation for continued growth. Prior to becoming President in July 2012, Mr. Stone served in several leadRobert Stone, JD

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

ADCETRIS® (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

The safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established. The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

The ASCO Post

Renal impairment

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

ership roles at City of Hope. He was the initial President and Executive Officer of the City of Hope Medical Foundation, an entity launched in June 2011 to increase collaboration between physicians and staff and enable more coordinated care for patients. As Chief Strategy and Administrative Officer, Mr. Stone recently led the creation and development of the organization’s 10-year strategic plan. He also previously served as City of Hope’s General Counsel and Secretary. He earned his law degree at the University of Chicago Law School. “We look forward to working with Robert to implement our new strategic plan and to continue the progress made under Michael’s superb guidance,” Ms. Biller said. “Michael’s integrity, wisdom, and personal commitment to our mission have helped us forge a path of distinction for the future while maintaining our standard of excellence that is recognized and respected around the world.” n

General dosing information

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Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS and its logo, SeaGen Secure and its logo, Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2013 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2011/0150c

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ASCOPost.com | MARCH 15, 2013

PAGE 91

In Memoriam

Jane Cooke Wright, MD, ASCO Cofounder, Dies at 93 By Ronald Piana

Jane Cooke Wright, MD

he practice of oncology advances incrementally; each step forward, no matter how painfully small at times, leads to the next. The oncology community readily offers tribute to predecessors in the field who took those first steps into the uncharted regions of cancer care, without which today’s successes would never have been possible. So it is fitting that, with sadness, we offer tribute to a doctor who left an indelible imprint on the treatment of people with cancer. Jane Cooke Wright, MD, died on February 19, 2013. She was 93.

Early Life and Career Born in 1919 in New York, Dr. Wright came of age during the vibrant cultural movement known as the Harlem Renaissance. Her mother was a schoolteacher and her father was a physician, one of the first African-Americans to graduate from Harvard Medical School. Dr. Wright’s robust academic pursuits were balanced with a zest for the arts and sports; she swam competitively during her years at Smith College. An art major at first, Dr. Wright switched to pre-med. She received her MD degree from New

York Medical School in 1945, and did her internship at Bellevue Hospital in New York. Two years later she married attorney David Dallas Jones, Jr, with whom she had two daughters. Her father’s continuing influence proved to be career-shaping. After her internship at Bellevue, Dr. Wright continued her training at Harlem Hospital, where her father was the founding Director of the hospital’s Cancer Research Foundation. In 1949, her father asked her to join the Foundation, and her interest in cancer research took a significant leap forward. The father and daughter team

used to cross-reference information from patients and tissue culture response to drugs. Her groundbreaking work caught the attention of policymakers on Capitol Hill, and in 1964, President Lyndon Johnson invited Dr. Wright to join the subcommittee of the President’s Commission on Heart Disease, Cancer, and Stroke. Her suggestions led to the establishment of nationwide regional cancer centers.

Role in Founding ASCO As befits a career filled with firsts, in 1964 Dr. Wright was one of ASCO’s founding members. At that time, she was

Coming together as a group we could improve quality of care, because knowledge is power, and sharing information among ourselves … would give us the greatest chance of increasing awareness and saving lives. —Jane Cooke Wright, MD

did basic bench research in leukemia, testing various agents in mouse models. After seeing activity, they began treating patients with early chemotherapies. Compelled by a desire to broaden her scope of cancer care, Dr. Wright moved on in 1955, continuing her research interests at New York University Bellevue Medical Center. In 1967, she became head of the Cancer Chemotherapy Department and Professor of Surgery at New York Medical College, where she created a program to teach physicians how to use chemotherapy and conduct clinical research. Her research in new chemotherapy techniques and drug interactions led to the establishment of a database that was

sometimes referred to as “the mother of chemotherapy,” a tribute to her early work in the emerging field. She was elected as the organization’s first Secretary-Treasurer, a position she held until 1967. A photograph of ASCO’s seven original founders, six white men and one young African-American woman, all of diverse backgrounds, reflects a profound storyline that held true throughout Dr. Wright’s life. Her countenance conveys no trace of loneliness at being the only woman and only African-American. Instead, she portrays unflinching unity with her colleagues and ASCO’s original charter—the common concern for the patient with cancer. Dr. Wright spoke of that sense of uni-

 In Memoriam

Jane Cooke Wright November 17, 1919 - February 19, 2013 

ty: “Coming together as a group we could improve quality of care, because knowledge is power, and sharing information among ourselves … would give us the greatest chance of increasing awareness and saving lives.”

Fighting the Good Fight Her long career would be marked throughout by her continued work in the oncology community and her association with leading organizations such as ASCO and the American Association for Cancer Research (AACR), which, in 2006, established the AACR-Minorities in Cancer Research Jane Cooke Wright Lectureship. Its first recipient, Olufunmilayo I. Olopade, MD, a Nigerian scientist and researcher, remarked that she was particularly impressed by the work Dr. Wright did “as a woman of color in the 1960s, and how progressive ASCO was to embrace her as an officer.” In 2011, ASCO and the Conquer Cancer Foundation formally recognized Dr. Wright’s contributions to the field of oncology through the creation of the Jane C. Wright, MD, Young Investigator Award. In a 2010 interview, Dr. Wright said that the best advice she ever received was from her father, who told her to never give up the good fight, never fear failure, and know that to help others in a worthy mission is a noble goal for one’s life. When asked what advice she would give oncologists and ASCO members today, she said, “I would tell ASCO members to work hard, persevere, collaborate with one another, be pioneers in the field, and keep up the good fight.” n

The ASCO Post | MARCH 15, 2013

PAGE 92

News

Survey Shows Public’s Knowledge of Cancer Progress Is Rising, But Myths Persist By Jo Cavallo

eople are more optimistic today about their chances of surviving cancer, according to findings from a new international survey commissioned by Lilly Oncology. The phone survey of 4,341 individuals (including people in the general population, cancer survivors, and caregivers) in six countries (the United States, France, Germany, Italy, Japan, and the United Kingdom) found that a near majority (48%) of respondents do not think a cancer diagnosis is a death sentence. Americans had the most optimistic outlook, with a whopping 65% of respondents saying they do not believe that cancer always leads to death.

Attitudes about Clinical Trials Perhaps even more surprising, a clear majority of respondents (74%) said they would be willing to participate in clinical trials. Other sizable majorities agreed that “Patients needed

cer patients actually enroll in clinical trials, according to the American Cancer Society.1 The willingness to enter clinical trials dropped off considerably when obstacles like cost and inconvenience were introduced. “This was one of the most important findings in the survey, and it is a point that needs to be looked at by a multi-stakeholder group, including health-care regulators and policymakers, because the pharmaceutical industry alone cannot solve this problem,” said Newton F. Crenshaw, Vice President of Lilly Oncology. “We all have to do a better job and think of some fresh ways to get people into clinical trials. We need to remove patients’ cultural concerns and their suspicions and worries over costs and inconvenience.”

Desire for Personalized Medicine While nearly 6 in 10 respondents

We all have to do a better job and think of some fresh ways to get people into clinical trials. We need to remove patients’ cultural concerns and their suspicions and worries over costs and inconvenience —Newton F. Crenshaw

more opportunities to participate” in clinical trials and that they would even be willing to participate in clinical studies if it could only benefit future patients. In the United States, however, the reality is that fewer than 5% of can-

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said they were satisfied with the amount of progress made in the fight against cancer over the past 2 decades, large majorities—73% of Americans and 83% of Japanese people surveyed—agreed that it takes too long

for new cancer therapies to reach patients. In every country except Japan, most agreed that progress in cancer research would be slowed due to a poor economy. Interestingly, while 62% of respondents agreed that the same cancer medication can produce very different results in patients with a similar diagnosis, only one-third overall and 48% of Americans are aware of personalized medicine. Once the concept of personalized medicine was explained, however, 85% said that doctors needed to discuss customized treatment with every patient, and 70% agreed that they would want to be tested for personalized medicine even if it might not work for them.

Myths About Cancer Among the prevailing myths surrounding cancer is that it is a single disease, with just a slight majority (51%) correctly stating that cancer comprises many different diseases that can appear in different parts of the body. “When you are a cancer patient or a caregiver for a cancer patient, you begin to understand how different and how intricate this disease is, so the fact that there are still people who believe that cancer is a monolithic disease is a myth we ought to dispel,” said Mr. Crenshaw, a survivor of large diffuse B-cell nonHodgkin lymphoma. Large numbers of respondents also underestimated the amount of time it takes to bring a new cancer drug to market and at least two-thirds—and nearly three-quarters of Americans— believed that the cost of researching

and developing a new cancer therapy is $100 million or less. (Studies on estimates of the actual cost of bringing a new drug to market vary widely at between $1.3 billion and $12 billion.2) The impact of a cancer diagnosis on family and friends ranked as the top fear cited by 67% of respondents, 1 percentage point above fear of death, and followed closely by inability to pay for treatment (65%).

Remedying Misperceptions According to Mr. Crenshaw, Lilly Oncology plans to use the information from the survey to spur a dialogue among health-care policymakers, cancer survivors, and other stakeholders to remedy the misperceptions of cancer and cancer care detailed in the survey and help speed innovation in more effective therapies. For more information on the PACE (Patient Access to Cancer care Excellence) Cancer Perception Index: A Six-Nation, Public Opinion Survey of Cancer Knowledge and Attitudes, visit pacenetwork.com. n

Disclosure: Mr. Crenshaw is Vice President of Lilly Oncology.

References 1. American Cancer Society: Clinical trials: What you need to know. Available at www.cancer.org. Accessed February 27, 2013. 2. Herper M: The truly staggering cost of inventing new drugs. Forbes. February 10, 2012. Available at forbes.com. Accessed February 27, 2013.

website at ASCOPost.com

Up the AntiEGFR Start ERBITUX® (cetuximab) in 1st-Line I N D I C AT I O N S Head and Neck Cancer—ERBITUX is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck Colorectal Cancer—ERBITUX is indicated for the treatment of KRAS mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use, in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer EGFR=epidermal growth factor receptor.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Approximately 90% of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. In 3 patients with prior history of coronary artery disease, death occurred 27, 32, and 43 days after the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX. Fatal cardiac disorders and/or sudden death occurred in 7 (3%) of the 219 patients with squamous cell carcinoma of the head and neck treated with platinum-based therapy with 5-fluorouracil (5-FU) and European Union (EU)-approved cetuximab as compared to 4 (2%) of the 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin — Carefully consider the use of ERBITUX in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks — Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

START WITH THE EXTREME

Regimen

EXTREME=ERBITUX® (cetuximab) in first-line Treatment of REcurrent or MEtastatic head and neck cancer. EXTREME Regimen=EU-approved cetuximab combined with platinum-based therapy with 5-FU.

The First Regimen Approved in 30 Years With Extended Overall Survival for Recurrent Locoregional or Metastatic SCCHN EXTREME REGIMEN (n=222)1

PLATINUM-BASED THERAPY WITH 5-FU (n=220)1

EXTENDED Median Overall Survival

(OS) (Primary Endpoint)

10.1 MONTHS

36% IMPROVEMENT IN OS*

7.4

MONTHS

HR=0.80 (95% CI: 0.64–0.98); p=0.034

IMPROVED Objective Response Rates (Reduced Tumor Size)†

20%

36%

PATIENTS

OR=2.33 (95% CI: 1.50–3.60); p=0.0001

PROLONGED Median Progression-Free Survival

5.5

MONTHS

3.3

MONTHS

HR=0.57 (95% CI: 0.46–0.72); p<0.0001 * Relative improvement in median overall survival for the EXTREME regimen was ([10.1-7.4]/7.4) x 100%=36%.1 †

Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 SCCHN=squamous cell carcinoma of the head and neck; CT=platinum-based therapy with 5-FU; OR=odds ratio; CI=confidence interval; HR=hazard ratio.

The EXTREME Study was an open-label, randomized (1:1), multicenter, controlled clinical trial that compared EU-approved cetuximab + CT vs CT alone. Choice of platinum therapy (cisplatin or carboplatin) was up to the treating physician. Sixty-four percent of patients received cisplatin therapy and 34% received carboplatin as initial therapy. Approximately 15% of the patients in the cisplatin-alone arm switched to carboplatin during the treatment period. In exploratory subgroup analyses of the EXTREME Study by initial platinum therapy (cisplatin or carboplatin), for patients (n=284) receiving cetuximab plus cisplatin with 5-FU compared to cisplatin with 5-FU alone, the difference in median overall survival was 3.3 months (10.6 vs 7.3 months, respectively; HR=0.71 [95% CI: 0.54–0.93]). The difference in median progression-free survival was 2.1 months (5.6 vs 3.5 months, respectively; HR=0.55 [95% CI: 0.41–0.73]). The objective response rate was 39% and 23%, respectively (OR=2.18 [95% CI: 1.29–3.69]). For patients (n=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months (9.7 vs 8.3 months; HR=0.99 [95% CI: 0.69–1.43]). The difference in median progression-free survival was 1.7 months (4.8 vs 3.1 months, respectively; HR=0.61 [95% CI: 0.42–0.89]). The objective response rate was 30% and 15%, respectively (OR=2.45 [95% CI: 1.10–5.46]).1 The EXTREME Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in these studies; these pharmacokinetic data, together with the results of the EXTREME Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in SCCHN.1

IMPORTANT SAFETY INFORMATION (continued) Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms. Permanently discontinue ERBITUX for confirmed ILD Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with carcinomas of the head and neck receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU (CT) (n=219) versus CT alone (n=215) (incidence ≥40%) were acneiform rash (70% vs 2%), nausea (54% vs 47%), and infection (44% vs 27%). The most common grade 3/4 adverse reactions for cetuximab in combination with CT (≥10%) versus CT alone included: infection (11% vs 8%). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX

START WITH THE CRYSTAL

Regimen

CRYSTAL=Cetuximab combined with iRinotecan inotecan in first-line therapY therapY for metaSTatic metaST STatic colorectAL colorectAL cancer. CRYSTAL Regimen=EU-approved cetuximab + FOLFIRI; FOLFIRI=irinotecan, 5-fluorouracil, and leucovorin.

The First and Only Biomarker-Directed Therapy for Newly Diagnosed KRAS Mutation-Negative (Wild-Type) EGFR-Expressing mCRC1 ALL-RANDOMIZED PATIENT POPULATION1 CRYSTAL Regimen (n=608)

Median Overall Survival*

KRAS WILD-TYPE SUBPOPULATION1 P O S T- H O C A N A LY S I S

FOLFIRI alone (n=609)

CRYSTAL Regimen (n=320)

18.5

23.5

(95% CI: 18–21)

(95% CI: 17–20)

(95% CI: 21–26)

MONTHS

HR=0.88 (95% CI: 0.78–1.0)

Objective Response Rates (Reduced Tumor Size)‡

Median Progression-Free Survival

EXTENDED

19.6 MONTHS

46%

FOLFIRI alone (n=356)

19.5 MONTHS

(95% CI: 17–21)

HR=0.80 (95% CI: 0.67–0.94)†

57%

38%

IMPROVED

39%

PATIENTS

(95% CI: 42–50)

(95% CI: 34–42)

(95% CI: 51–62)

(95% CI: 34–44)

8.9

8.1

9.5

MONTHS

(95% CI: 8.0–9.4)

(95% CI: 7.6–8.8)

PROLONGED

8.1

MONTHS

(95% CI: 8.9–11.1)

(95% CI: 7.4–9.2)

HR=0.85 (95% CI: 0.74–0.99); p=0.0358

HR=0.70 (95% CI: 0.57–0.86)

In all randomized patients, overall survival was not significantly different at the planned, final analysis based on 838 events (HR=0.93 [95% CI: 0.8–1.1]; p=0.327). Limitation of Use: ERBITUX is not indicated for treatment of KRAS mutation-positive colorectal cancer. •The primary endpoint for the study was progression-free survival in the all-randomized patient population. * Post-hoc updated overall survival analysis based on an additional 162 events.1

Not significantly different.1 Objective response=complete response + partial response; tumor size reduction ≥50% (modified WHO criteria).2,3 § Based on the stratified log-rank test.1 mCRC=metastatic colorectal cancer; CI=confidence interval; HR=hazard ratio. †

‡

The CRYSTAL Study was a Phase 3, open-label, randomized, multicenter study of 1217 patients with EGFR-expressing mCRC. Patients were randomized (1:1) to receive either EU-approved cetuximab in combination with FOLFIRI (the CRYSTAL Regimen) or FOLFIRI alone as first-line treatment. KRAS mutational status was available for 1079/1217 (89%) of the patients: 676 (63%) patients had KRAS mutation-negative (wild-type) tumors. Post-hoc analyses of efficacy data were performed on patient subgroups defined by KRAS mutation status.1 The CRYSTAL Study was conducted outside the U.S. using European Union (EU)-approved cetuximab as the clinical trial material. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in this study; these pharmacokinetic data, together with the results of the CRYSTAL Study, and other clinical trial data, establish the efficacy of ERBITUX at the recommended dose in mCRC.1

IMPORTANT SAFETY INFORMATION (continued) Select Adverse Reactions ■ The most frequent adverse reactions seen in patients with KRAS mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer treated with EU-approved cetuximab + FOLFIRI (n=317) versus FOLFIRI alone (n=350) (incidence ≥50%) were acne-like rash (86% vs 13%) and diarrhea (66% vs 60%). The most common grade 3/4 adverse reactions (≥10%) included: neutropenia (31% vs 24%), acne-like rash (18% vs <1%), and diarrhea (16% vs 10%). U.S.-licensed ERBITUX provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided above are consistent in incidence and severity of adverse reactions with those seen for ERBITUX in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX Please see brief summary of Full Prescribing Information and Important Safety Information including Boxed WARNINGS, on adjacent pages.

UP THE ANTI-EGFR

Dermatologic Toxicities ■ In clinical studies of ERBITUX (cetuximab), dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneiform rash occurred in 76-88% of 1373 patients receiving ERBITUX in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1-17% of patients —Acneiform rash usually developed within the first 2 weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae —Sun exposure may exacerbate these effects Electrolyte Depletion ■ Hypomagnesemia occurred in 55% of 365 patients receiving ERBITUX in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC grades 3 & 4) in 6-17%. In Study 2 the addition of EU-approved cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs 6%) and of grade 3–4 hypomagnesemia (7% vs 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs 4%). No patient experienced grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia, and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy —Replete electrolytes as necessary Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX Adverse Reactions ■ The most serious adverse reactions associated with ERBITUX are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) across all studies were cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection

The ERBITUX (cetuximab) Patient Support Program CONTACT your sales representative or call 1-800-805-1058 (8 AM-8 PM EST, M-F) to receive patient education materials, enrollment information, and forms

Phone 1-800-861-0048 or Fax 1-888-776-2370 8 AM to 8 PM EST, M-F Please see enclosed Full Prescribing Information, including Boxed WARNINGS. References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company; July 2012. 2. Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981;47(1):207-214. 3. Van Cutsem E, Köhne C-H, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011-2019.

SCAN QR CODE for more information. By scanning the QR code, you are confirming you are a US Healthcare Professional.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2012 ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb Company, Princeton, NJ 08543, U.S.A. All rights reserved. ERBITUX is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company. 693US13BR00168-02-01 11/12

UP THE ANTI-EGFR

ERBITUX® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: SERIOUS INFUSION REACTIONS and CARDIOPULMONARY ARREST Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions, Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Dosage and Administration (2.4) in Full Prescribing Information, Warnings and Precautions.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated with Erbitux and radiation therapy in Study 1 and in 3% of patients with squamous cell carcinoma of the head and neck treated with European Union (EU)-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in Study 2. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux administration. [See Warnings and Precautions, Clinical Studies (14.1) in Full Prescribing Information.] INDICATIONS AND USAGE Squamous Cell Carcinoma of the Head and Neck (SCCHN): Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux is indicated in combination with platinum-based therapy with 5-FU for the first-line treatment of patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.] Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.] K-Ras Mutation-negative, EGFR-expressing Colorectal Cancer: Erbitux is indicated for the treatment of K-Ras mutation-negative (wild-type), epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use [see Dosage and Administration (2.2) in Full Prescribing Information, Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information].

• in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment,

• in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy,

• a s a single agent in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. [See Warnings and Precautions, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information.]

Limitation of Use: Erbitux is not indicated for treatment of K-Ras mutation-positive colorectal cancer [see Warnings and Precautions, Clinical Studies (14.2) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Infusion Reactions: Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in Studies 1, 3, 5, and 6 receiving Erbitux, with fatal outcome in 1 patient. [See Clinical Studies (14.1, 14.2) in Full Prescribing Information.] Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines. Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions. Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning, Dosage and Administration (2.4) in Full Prescribing Information.] Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in Study 1. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. In Study 2, fatal cardiac disorders and/or sudden death occurred in 7 (3%) of 219 patients treated with EU-approved cetuximab and platinum-based therapy with 5-FU as compared to 4 (2%) of 215 patients treated with chemotherapy alone. Five of these 7 patients in the chemotherapy plus cetuximab arm received concomitant cisplatin and 2 patients received concomitant carboplatin. All 4 patients in the chemotherapy-alone arm received cisplatin. Carefully consider use of Erbitux in combination with radiation therapy or platinum-based therapy with 5-FU in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning, Warnings and Precautions.] Pulmonary Toxicity: Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in Studies 1, 3, and 6, as well as other studies, in colorectal cancer and head and neck cancer. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity: Dermatologic toxicities, including acneiform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneiform rash occurred in 76–88% of 1373 patients receiving Erbitux in Studies 1, 3, 5, and 6. Severe acneiform rash occurred in 1–17% of patients. Acneiform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dosage and Administration (2.4) in Full Prescribing Information.] Use of Erbitux in Combination With Radiation and Cisplatin: The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events. Hypomagnesemia and Electrolyte Abnormalities: In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of 365 patients receiving Erbitux in Study 5 and two other clinical trials in colorectal cancer and head and neck cancer, respectively, and was severe (NCI CTC Grades 3 and 4) in 6–17%. In Study 2, where EU-approved cetuximab was administered in combination with platinum-based therapy, the addition of cetuximab to cisplatin and 5-FU resulted in an increased incidence of hypomagnesemia (14% vs. 6%) and of Grade 3–4 hypomagnesemia (7% vs. 2%) compared to cisplatin and 5-FU alone. In contrast, the incidences of hypomagnesemia were similar for those who received cetuximab, carboplatin, and 5-FU compared to carboplatin and 5-FU (4% vs. 4%). No patient experienced Grade 3–4 hypomagnesemia in either arm in the carboplatin subgroup.

Erbitux0712PBS_7x9wip6.indd 1

The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux (cetuximab). Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary. K-Ras Testing in Metastatic or Advanced Colorectal Cancer Patients: Determination of K-Ras mutational status in colorectal tumors using an FDA-approved test indicated for this use is necessary for selection of patients for treatment with Erbitux. Erbitux is indicated only for patients with EGFR-expressing K-Ras mutation-negative (wild-type) mCRC. Erbitux is not an effective treatment for patients with colorectal cancer that harbor somatic mutations in codons 12 and 13 (exon 2). Studies 4 and 5, conducted in patients with colorectal cancer, demonstrated a benefit with Erbitux treatment only in the subset of patients whose tumors were K-Ras mutation-negative (wild-type). Erbitux is not effective for the treatment of K-Ras mutation-positive colorectal cancer as determined by an FDA-approved test for this use. [See Indications and Usage (1.2) in Full Prescribing Information, Clinical Pharmacology (12.1) in Full Prescribing Information, Clinical Studies (14.2) in Full Prescribing Information]. Perform the assessment for K-Ras mutation status in colorectal cancer in laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for the treatment of Erbitux. Epidermal Growth Factor Receptor (EGFR) Expression and Response: Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry. Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/ faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning, Warnings and Precautions.] • Cardiopulmonary arrest [See Boxed Warning, Warnings and Precautions.] • Pulmonary toxicity [See Warnings and Precautions.] • Dermatologic toxicity [See Warnings and Precautions.] • Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.] The most common adverse reactions in Erbitux clinical trials (incidence ≥25%) include cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. Across Studies 1, 3, 5, and 6, Erbitux was discontinued in 3–10% of patients because of adverse reactions. Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Erbitux in 1373 patients with SCCHN or colorectal cancer in randomized Phase 3 (Studies 1 and 5) or Phase 2 (Studies 3 and 6) trials treated at the recommended dose and schedule for medians of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.] Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient. Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients. Renal: Renal failure occurred in 1% of patients with colorectal cancer. Squamous Cell Carcinoma of the Head and Neck Erbitux in Combination with Radiation Therapy — Table 1 contains selected adverse reactions in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11). Table 1:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Locoregionally Advanced SCCHN Erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) Body System Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Body as a Whole Asthenia 56 4 49 5 29 1 13 1 Fevera Headache 19 <1 8 <1 15 3 2 0 Infusion Reactionb Infection 13 1 9 1 a 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, highc Aspartate Transaminase, highc 38 1 24 1 33 <1 24 0 Alkaline Phosphatase, highc Respiratory Pharyngitis 26 3 19 4 Skin/Appendages 87 17 10 1 Acneiform Rashd Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 a Includes cases also reported as infusion reaction. b Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”. c Based on laboratory measurements, not on reported adverse reactions, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone. d Acneiform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”. The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

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Late Radiation Toxicity — The overall incidence of late radiation toxicities (any grade) was higher in Erbitux (cetuximab) in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups. Study 2: EU-Approved Cetuximab in Combination with Platinum-based Therapy with 5-Fluorouracil — Study 2 used EU-approved cetuximab. Since U.S.-licensed Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided below may underestimate the incidence and severity of adverse reactions anticipated with Erbitux for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 2 contains selected adverse reactions in 434 patients with recurrent locoregional disease or metastatic SCCHN receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone in Study 2. Cetuximab was administered at 400 mg/m2 for the initial dose, followed by 250 mg/m2 weekly. Patients received a median of 17 infusions (range 1–89). Table 2:

Incidence of Selected Adverse Reactions (≥10%) in Patients with Recurrent Locoregional Disease or Metastatic SCCHN EU-Approved Cetuximab Platinum-based plus Platinum-based Therapy with Therapy with 5-FU 5-FU Alone (n=219) (n=215) System Organ Class Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients Eye Disorders Conjunctivitis 10 0 0 0 Gastrointestinal Disorders Nausea 54 4 47 4 Diarrhea 26 5 16 1 General Disorders and Administration Site Conditions Pyrexia 22 0 13 1 10 2 <1 0 Infusion Reactiona Infections and Infestations 44 11 27 8 Infectionb Metabolism and Nutrition Disorders Anorexia 25 5 14 1 Hypocalcemia 12 4 5 1 Hypokalemia 12 7 7 5 Hypomagnesemia 11 5 5 1 Skin and Subcutaneous Tissue Disorders 70 9 2 0 Acneiform Rashc Rash 28 5 2 0 Acne 22 2 0 0 Dermatitis Acneiform 15 2 0 0 Dry Skin 14 0 <1 0 Alopecia 12 0 7 0 a Infusion reaction defined as any event of “anaphylactic reaction”, “hypersensitivity”, “fever and/or chills”, “dyspnea”, or “pyrexia” on the first day of dosing. b Infection – this term excludes sepsis-related events which are presented separately. c Acneiform rash defined as any event described as “acne”, “dermatitis acneiform”, “dry skin”, “exfoliative rash”, “rash”, “rash erythematous”, “rash macular”, “rash papular”, or “rash pustular”. Chemotherapy = cisplatin + 5-fluorouracil or carboplatin + 5-fluorouracil For cardiac disorders, approximately 9% of subjects in both the EU-approved cetuximab plus chemotherapy and chemotherapy-only treatment arms in Study 2 experienced a cardiac event. The majority of these events occurred in patients who received cisplatin/5-FU, with or without cetuximab as follows: 11% and 12% in patients who received cisplatin/5-FU with or without cetuximab, respectively, and 6% or 4% in patients who received carboplatin/5-FU with or without cetuximab, respectively. In both arms, the incidence of cardiovascular events was higher in the cisplatin with 5-FU containing subgroup. Death attributed to cardiovascular event or sudden death was reported in 3% of the patients in the cetuximab plus platinum-based therapy with 5-FU arm and 2% in the platinum-based chemotherapy with 5-FU alone arm. Colorectal Cancer Study 4: EU-Approved Cetuximab in Combination with FOLFIRI — Study 4 used EU-approved cetuximab. U.S.-licensed Erbitux provides approximately 22% higher exposure to cetuximab relative to the EU-approved cetuximab. The data provided below for Study 4 is consistent in incidence and severity of adverse reactions with those seen for Erbitux in this indication. The tolerability of the recommended dose is supported by safety data from additional studies of Erbitux [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Table 3 contains selected adverse reactions in 667 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer receiving EU-approved cetuximab plus FOLFIRI or FOLFIRI alone in Study 4 [see Warnings and Precautions]. Cetuximab was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 26 infusions (range 1–224). Table 3:

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Table 3: (Continued)

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type) and EGFR-expressing, Metastatic Colorectal Cancera EU-Approved Cetuximab plus FOLFIRI FOLFIRI Alone (n=317) (n=350) Grades Grades Grades Body System Grades 1–4b 3 and 4 1–4 3 and 4 Preferred Term % of Patients Skin and Subcutaneous Tissue Disorders 86 18 13 <1 Acne-like Rashd Rash 44 9 4 0 Dermatitis Acneiform 26 5 <1 0 Dry Skin 22 0 4 0 Acne 14 2 0 0 Pruritus 14 0 3 0 Palmar-plantar Erythrodysesthesia Syndrome 19 4 4 <1 Skin Fissures 19 2 1 0 a Adverse reactions occurring in at least 10% of Erbitux (cetuximab) combination arm with a frequency at least 5% greater than that seen in the FOLFIRI arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion related reaction is defined as any event meeting the medical concepts of allergy/anaphylaxis at any time during the clinical study or any event occurring on the first day of dosing and meeting the medical concepts of dyspnea and fever or by the following events using MedDRA preferred terms: “acute myocardial infarction”, “angina pectoris”, “angioedema”, “autonomic seizure”, “blood pressure abnormal”, “blood pressure decreased”, “blood pressure increased”, “cardiac failure”, “cardiopulmonary failure”, “cardiovascular insufficiency”, “clonus”, “convulsion”, “coronary no-reflow phenomenon”, “epilepsy”, “hypertension”, “hypertensive crisis”, “hypertensive emergency”, “hypotension”, “infusion related reaction”, “loss of consciousness”, “myocardial infarction”, “myocardial ischaemia”, “prinzmetal angina”, “shock”, “sudden death”, “syncope”, or “systolic hypertension”. d Acne-like rash is defined by the events using MedDRA preferred terms and included “acne”, “acne pustular”, “butterfly rash”, “dermatitis acneiform”, “drug rash with eosinophilia and systemic symptoms”, “dry skin”, “erythema”, “exfoliative rash”, “folliculitis”, “genital rash”, “mucocutaneous rash”, “pruritus”, “rash”, “rash erythematous”, “rash follicular”, “rash generalized”, “rash macular”, “rash maculopapular”, “rash maculovesicular”, “rash morbilliform”, “rash papular”, “rash papulosquamous”, “rash pruritic”, “rash pustular”, “rash rubelliform”, “rash scarlatiniform”, “rash vesicular”, “skin exfoliation”, “skin hyperpigmentation”, “skin plaque”, “telangiectasia”, or “xerosis”. Erbitux Monotherapy — Table 4 contains selected adverse reactions in 242 patients with K-Ras mutation-negative (wild-type), EGFR-expressing, metastatic colorectal cancer who received best supportive care (BSC) alone or with Erbitux in Study 5 [see Warnings and Precautions]. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 17 infusions (range 1–51). Table 4:

Incidence of Selected Adverse Reactions Occurring in ≥10% of Patients with K-Ras Mutation-negative (Wild-type), EGFR-expressing, Metastatic Colorectal Cancer Treated with Erbitux Monotherapya Erbitux plus BSC BSC alone (n=118) (n=124) Body System Grades Grades Grades Grades Preferred Term 1–4b 3 and 4 1–4 3 and 4 % of Patients Dermatology/Skin Rash/Desquamation 95 16 21 1 Dry Skin 57 0 15 0 Pruritus 47 2 11 0 Other-Dermatology 35 0 7 2 Nail Changes 31 0 4 0 Constitutional Symptoms Fatigue 91 31 79 29 Fever 25 3 16 0 18 3 0 0 Infusion Reactionsc Rigors, Chills 16 1 3 0 Pain Pain-Other 59 18 37 10 Headache 38 2 11 0 Bone Pain 15 4 8 2 Pulmonary Dyspnea 49 16 44 13 Cough 30 2 19 2 Gastrointestinal Nausea 64 6 50 6 Constipation 53 3 38 3 Diarrhea 42 2 23 2 Vomiting 40 5 26 5 Stomatitis 32 1 10 0 Other-Gastrointestinal 22 12 16 5 Dehydration 13 5 3 0 Mouth Dryness 12 0 6 0 Taste Disturbance 10 0 5 0 Infection Infection without neutropenia 38 11 19 5 Musculoskeletal Arthralgia 14 3 6 0 Neurology Neuropathy-sensory 45 1 38 2 Insomnia 27 0 13 0 Confusion 18 6 10 2 Anxiety 14 1 5 1 Depression 14 0 5 0 a Adverse reactions occurring in at least 10% of Erbitux plus BSC arm with a frequency at least 5% greater than that seen in the BSC alone arm. b Adverse reactions were graded using the NCI CTC, V 2.0. c Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, sweating, tremors, shaking, drug fever, or other hypersensitivity reaction) recorded by the investigator as infusion-related. Erbitux in Combination with Irinotecan — The most frequently reported adverse reactions in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneiform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse reactions included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneiform rash (14%). Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

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The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux (cetuximab) with the incidence of antibodies to other products may be misleading. Postmarketing Experience: The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure. • Aseptic meningitis DRUG INTERACTIONS A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C — There are no adequate and well-controlled studies of Erbitux in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48). Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area). Nursing Mothers: It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux. Pediatric Use: The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Erbitux was administered once-weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were identified in pediatric patients. The pharmacokinetic profiles of cetuximab between the two age groups were similar at the 75 and 150 mg/m2 single dose levels. The volume of the distribution appeared to be independent of dose and approximated the vascular space of 2–3 L/m2. Following a single dose of 250 mg/m2, the geometric mean AUC0-inf (CV%) value was 17.7 mg•h/mL (34%) in the younger age group (1–12 years, n=9) and 13.4 mg•h/mL (38%) in the adolescent group (13–18 years, n=6). The mean half-life of cetuximab was 110 hours (range 69 to 188 hours) for the younger age group, and 82 hours (range 55 to 117 hours) for the adolescent age group.

M Erbitux0712PBS_7x9wip6.indd 3

Geriatric Use: Of the 1662 patients who received Erbitux (cetuximab) with irinotecan, FOLFIRI or Erbitux monotherapy in six studies of advanced colorectal cancer, 588 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. OVERDOSAGE The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area). Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans. Animal Pharmacology and/or Toxicology: In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment. PATIENT COUNSELING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems. • Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy. • That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy. • To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux. Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company. Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Rev July 2012 693US12PBS11501

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News Health Information Technology

IBM’s Watson Goes Through Basic Training in Oncology By Jo Cavallo

hile IBM’s Watson supercomputer may have defeated two former champions on the TV game show Jeopardy! 2 years ago, it is now facing its greatest challenge yet: deciphering huge amounts of scientific data and interpreting clinical information to help oncologists make personalized evidence-based treatment decisions for their patients—all in the blink of an eye. Named after Thomas J. Watson, Sr, the founder of IBM, Watson is an artificial intelligence computer system that uses natural language processing software to understand written language. Using probabilistic algorithms, Watson reads and understands millions of pages of text to find information relevant to clinicians’ queries and then generates multiple possibilities they can use in making treatment decisions. Watson is considered knowledge-driven support, which means the knowledge exists but needs to be found and identified, as compared to data-driven decision support, which generates evidence used for decisions from structured data that is stored in places, such as electronic medical records or other databases. “There are so many articles being published all the time, no one person can keep up with the volume,” said Martin S. Kohn, MD, Chief Medical Scientist, Care Delivery

vention, and then looking at all the literature and finding the appropriate information that is relevant to the decision the physician has to make.”

Oncology Training Underway According to Dr. Kohn, when Watson appeared on Jeopardy! it was able to read and understand 200 million pages of text in 3 seconds. Now, Watson is undergoing basic training in oncology at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York. The first applications for Watson are in lung and breast cancers, and other cancers will follow. Memorial Sloan-Kettering is using its own de-identified historical records to “teach” Watson relevant data elements to consider, such as results from blood tests; pathology and imaging reports detailing type, size, and location of a patient’s tumor; the presence of genetic mutations; whether the cancer has metastasized; and other specific details about medical histories, including comorbidities. Watson’s task then will be to offer physicians a list of treatment options, including clinical trials, based on the expertise of MSKCC physicians and evidence-based guidelines, as well as a confidence rating for each option. Initially, treatment options will focus on appropriate chemotherapeutics for a patient, and will not include suggestions on radiation therapy or surgery.

Collaborative access to Watson for the patient and the patient’s care team could enable the patient to ask questions and get information that could be shared with the patient’s medical team. —Martin S. Kohn, MD

Systems at IBM Research-Watson. “The National Library of Medicine catalogued 700,000 new articles in 2010. Watson understands language well enough to infer the nature of a question posed, whether it is about making a diagnosis, choosing a medication, or doing a test or inter-

Testing for the lung cancer prototype should be finalized by midyear. Once testing is completed at MSKCC, beta versions of the system will be distributed to other physicians and hospitals with an initial commercial offering before the end of the year.

Computing with a Personal Touch Leading the Watson healthcare system development effort at MSKCC is Mark G. Kris, MD, Chief of the Thoracic Oncology Service. According to Dr. Kris, the clinical decision support tool will be useful to oncologists in several areas, including providing patients with the assurance that their treatment plan is based on the most up-to-date,

the physician’s decisions are evidencebased,” noted Dr. Kris.

Tailoring Care While knowledge gained in molecular biology and genetics over the last 2 decades have provided physicians with potential strategies for targeting specific molecular alterations in cancerous tumors, it has also added to the complexity of diagnosing and treating individual patients. With Watson, said

If you have a patient with that gene mutation sitting in front of you, you need to be able to have the most current information to prescribe the most effective therapy. That’s the kind of thing Watson can do. —Mark G. Kris, MD

relevant laboratory and clinical trial data published in medical journals and determined to be the most effective for their specific cancer type and clinical status. “Watson can provide a sort of second-opinion for patients because their oncologists are making treatment decisions that are benchmarked against a very broad and expansive network that is looking at all the medical data,” said Dr. Kris. Watson can also customize treatment options based on information in a patient’s electronic health record. “Patients don’t want care that is good for anybody, they want care that is best for them. Watson will ultimately delve into a patient’s medical record and look for special characteristics and clinical nuances and benchmark them against other patients with similar records. It is counterintuitive to think that a computer, a machine, would actually facilitate more personalized care, but it can,” said Dr. Kris. Another benefit, said Dr. Kris, is that Watson should also help speed up the health insurance preauthorizationapproval process for treatments and test procedures, or even render it obsolete. “From the payer’s standpoint, if Watson says a particular treatment choice is best, then the whole preauthorization process disappears because the insurer has the assurance that

Dr. Kris, oncologists and physicians who do not specialize in specific cancer subtypes will be able to easily access current information and integrate it into their patients’ treatment plans. “Most non–small cell lung cancer patients have one genomic alteration, EGFR, that drives their cancer, and we know that EGFR is sensitive to erlotinib (Tarceva). But at ASCO’s Annual Meeting last June, an abstract was presented showing that if a patient has an EGFR mutation with exon 20 insertion, erlotinib won’t work and chemotherapy is a better choice.1 That is a very specific piece of information, and you can’t expect every oncologist to know it. But if you have a patient with that gene mutation sitting in front of you, you need to be able to have the most current information to prescribe the most effective therapy. That’s the kind of thing Watson can do. It can look for those very rare mutations and those exceptions to the rule and then match them up,” said Dr. Kris.

Empowering Patients Although Watson’s initial development phase in cancer care is centered on making it an innovative and crucial decision-support tool for oncologists, as its functionality evolves, it may also become an important support tool for patients. continued on page 101

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News

Study Shows New Approach Connecting Smokers to Quit Lines Increases Smoking Cessation Treatment Enrollment

elf-identified smokers directly connected to a tobacco cessation quit line are 13 times more likely to enroll in a treatment program as compared to smokers who are handed a quit line referral card and encouraged to call on their own, according to a new study published online in JAMA Internal Medicine.1

Ask-Advise-Connect Led by researchers at The University of Texas MD Anderson Cancer Center, the study evaluated the efficacy of an “Ask-Advise-Connect” approach to linking smokers to evidence-based tobacco cessation treatment. The approach is based on the current recommended standard of care in the field, as described in the Treating Tobacco Use and Dependence Clinical Practice Guideline. Ask-Advise-Connect, MD Anderson’s collaborative study with the Texas Quitline and Kelsey-Seybold Clinic streamlined and automated the process of connecting smokers with treatment using their electronic health record (EHR). “Approximately 70% of smokers see their primary care physician at least once a year, so health-care settings provide an ideal infrastructure for linking smokers with cessation treatment,” said Jennifer Irvin

IBM’s Watson continued from page 100

“One of the thrusts of the future of health care is the idea that all the people involved in the decision-making process—the physician, physician assistants, nurses, the patient, and the patient’s family—can benefit from this kind of support,” said Dr. Kohn. “In the future, collaborative access to Watson for the patient and the patient’s care team could enable the patient to ask questions and get information that could be shared with the patient’s medical team. That could really help move us along the direction of the empowered, knowledgeable patient who is an active participant in the decisionmaking for his or her health care.” Because Watson would read information from patients’ medical records, it

Vidrine, PhD, Associate Professor in the Department of Health Disparities Research at MD Anderson and lead investigator on the study.

Study Details In this study, licensed vocational nurses and medical assistants were trained to ask all patients about their smoking status at the time vital signs were collected, and to record this information in the EHR. Smokers were also given advice on quitting and offered either a connection or referral to the quit line, depending on clinic randomization.

The process was the same in both clinic settings except for the method used to link smokers with the quit line. In Ask-Advise-Connect clinics, contact information for patients willing to be connected to the quit line was pulled directly from the EHR and sent to the MD Anderson research team. The information was then sent to the Texas Quitline within 24 hours, and patients were called by quit line staff within 48 hours of receiving their information. In Ask-Advise-Refer clinics, the names and phone numbers of patients willing to accept a referral card were sent to the MD Anderson research

Smoking Cessation Treatment ■■ A new tobacco cessation approach, Ask-Advise-Connect, streamlines and automates the process of connecting smokers with treatment using their electronic health record (EHR).

■■ Study results indicated that 7.8% of all smokers identified at Ask-AdviseConnect clinics enrolled in treatment with a quit line compared to 0.6% of all smokers identified at Ask-Advise-Refer clinics, a 13-fold increase in treatment enrollment.

■■ The findings reflect one of the highest rates of tobacco cessation treatment enrollment reported in the literature to date.

Ten clinics participated in the study with five clinics randomized to implement Ask-Advise-Connect, and the others randomized to implement a control condition called Ask-Advise-Refer.

team. Patients were encouraged to call the quit line on their own, and patients who called were tracked by quit line staff. Both approaches were implemented for 9 months.

could also provide patients with an explanation of why a specific treatment is being

LinQ. This system will have the ability to assemble and analyze data from the electronic health records of millions of cancer patients; provide real-time, standardized, clinical decision support integration within a demonstration electronic health record; demonstrate value-added tools, including the ability to measure a clinician’s performance against a subset of Quality Oncology Practice Initiative (QOPI) measures in real time; and create new ways of exploring clinical data and hypothesis generation. The testing of a breast cancer–specific prototype for CancerLinQ is underway. (See “Building CancerLinQ,” an interview with Clifford A. Hudis, MD, on page 1 in this issue of The ASCO Post.) “Systems like Watson and CancerLinQ provide the kind of technologi-

These tools are physician advisors, they are not decision-makers. —Mark G. Kris, MD

recommended and details of potential side effects and how to manage those effects. Ideally, the information could then be printed or sent electronically to the patient’s mobile device, added Dr. Kris.

ASCO’s Rapid Learning System Last November, ASCO unveiled its own rapid learning system, Cancer-

Results The smoking status of more than 32,000 patients was assessed and recorded in the EHR, and 3,336 patients reported current smoking, a smoking prevalence of 11.2%. The study’s primary outcome was impact, defined as the proportion of all identified smokers who enrolled in smoking cessation treatment with the quit line, said Dr. Vidrine. The results indicated that 7.8% of all smokers identified at Ask-Advise-Connect clinics enrolled in treatment with the quit line compared to 0.6% of all smokers identified at Ask-Advise-Refer clinics, reflecting a 13-fold increase in treatment enrollment. “The findings reflect one of the highest rates of tobacco cessation treatment enrollment reported in the literature to date,” said Dr. Vidrine. “Given that smoking is the leading cause of preventable morbidity and mortality in the United States, Ask-Advise-Connect has tremendous potential to have a large public health impact if adopted broadly by other health-care systems.” n Reference 1. Vidrine J, Shete S, Cao Y, et al: AskAdvise-Connect: A new approach to smoking treatment delivery in health cara settiongs. JAMA Intern Med. Early release online, February 25, 2013.

cal competition that will accelerate advancements in cancer care,” said Dr. Kris. “However, these tools are physician advisors, they are not decision-makers. Our vision is that these systems provide information that the physician and the patient can use together to arrive at the best treatment, keeping in mind both the goals of care and the patient’s wishes.” n

Disclosure: Dr. Kris currently holds fulltime employment for an entity having an investment, licensing, or other commercial interest in the subject matter under consideration.

Reference 1. Costa DB, Yasuda H, Sng NJ, et al: Sensitivity to EGFR inhibitors based on location of EGFR exon 20 insertion mutations within the tyrosine kinase domain of EGFR. 2012 ASCO Annual Meeting. Abstract 7523. Presented June 5, 2012.

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2013

2013 Oncology Meetings March Emerging Trends Conference: Reactivation of Hepatitis B March 21-22 • Arlington, Virginia For more information: www.aasld.org/additionalmeetings/ Pages/emergingtrends.aspx 5th Thyroid Neoplasms Conference March 21-23 • Houston, Texas For more information: www.mdanderson.org/conferences Community Oncology Journal’s 8th Annual Oncology Practice Summit March 21-23 • Las Vegas, Nevada For more information: onc.globalacademycme.com/ conferences/oncology-practicesummit-2013/conference-overview.html ASTRO Spring Refresher Course March 22-24 • Chicago, Illinois For more information: www.astro.org/springrefresher Highlights of ASH® in Asia March 23-24 • Shanghai, China For more information: www. hematology.org/meetings 23rd Annual National Interdisciplinary Breast Cancer Conference March 23-27 • Las Vegas, Nevada For more information: www.breastcare.org/

April IGCS Regional Meeting on Gynecologic Cancers April 11-13 • Bali, Indonesia For more information: www2.kenes.com/igcs2013

3rd ITLT Essen 2013 Interdisciplinary Treatment of Liver Tumors April 18-20 • Essen, Germany For more information: www.itlt.org The Arizona Clinical Oncology Society Spring Membership Conference April 19 • Phoenix, Arizona For more information: www.tacos-oncology.com/

The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com

Ultrasound in the New Millennium: The Cancer Patient April 19-20 • Houston, Texas For more information: www.mdanderson.org/conferences

State of the Art Techniques Symposium May 17-19 • San Antonio, Texas For more information: www.astro.org/ stateofthearttechniques

7th Conference on Experimental and Translational Oncology April 20-24 • Portoroz, Slovenia For more information: www.ceto.si

3rd International Symposium on Lung-Sparing Therapies for Malignant Pleural Mesothelioma May 18, 2013 • Santa Monica, California For more information: www.cme.ucla.edu/courses/

Highlights of ASH® in Latin America April 25-26 • Santiago, Chile For more information: www.hematology.org/meetings

May 2013 Annual Paris Melanoma Conference May 2-3 • Paris, France For more information: www.primeoncology.org/ parismelanoma2013 5th IMPAKT Breast Cancer Conference May 2-4 • Brussels, Belgium For more information: www.esmo.org

66th Urological Society of Australia and New Zealand Annual Scientific Meeting April 13-16 • Melbourne, Australia For more information: www.usanz2013.com

Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com

International Society for Extracellular Vesicles 2013 Conference April 17-20 • Boston, MA For more information: www.isevmeeting.org

European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org

5th Symposium on Cancer Metastasis and the Lymphovascular System and the 8th International Sentinel Node Society Congress May 27-29, 2013 • San Francisco, California For more information: www.sn-cancermets.org Targeting Cancer Drug Resistance May 28-30 • Chicago, Illinois For more information: www.cancer-drugresistance.com The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow

2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

June Molecular and Translational Oncology Workshop June 14-18 • Fort Myers, Florida For more information: www.cancereducationconsortium. org/programs_mtow.html 12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com 6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org 2nd International Breakthrough Breast Cancer Conference– Triple Negative Breast Cancer June 26-28 • London, United Kingdom For more information: www.breakthroughconference.org.uk

Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 13th World Congress of the European Association for Palliative Care May 30-June 2 • Prague, Czech Republic For more information: www.eapc-2013.org

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com continued on page 107

When hemoglobin fallsâ&#x20AC;Ś

For chemotherapy-induced anemia (CIA) in metastatic patients with Hb < 10 g/dL

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks*5 • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo†2,3 • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa CIA trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.3

INDICATION and LIMITATIONS OF USE Aranesp® (darbepoetin alfa) is for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Aranesp® is not for use: • In patients receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy • In patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • As a substitute for RBC transfusions in patients requiring immediate correction of anemia Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

RBC = red blood cell

Hb = hemoglobin

Q3W = once every three weeks

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs Increase the Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, Thrombosis of Vascular Access and Tumor Progression or Recurrence Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions • Use ESAs only for anemia from myelosuppressive chemotherapy, and discontinue upon completion of a chemotherapy course

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • Prescribers and hospitals must enroll in the ESA APPRISE Oncology Program to prescribe or dispense Aranesp® to patients with cancer; to enroll, visit www.esa-apprise.com or call 1-866-284-8089 for assistance Do not use Aranesp® in patients with uncontrolled hypertension; control blood pressure prior to and during treatment. Do not use Aranesp® in patients with pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs. If severe anemia and low reticulocyte count develop during treatment, withhold Aranesp® and evaluate for PRCA. Do not use Aranesp® in patients with history of serious allergic reactions to the product, which may include anaphylaxis, angioedema, bronchospasm, skin rash, and urticaria. Immediately discontinue Aranesp® if such a reaction occurs. Adverse reactions in ≥ 1% of patients treated with Aranesp® in clinical studies were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary on following page for additional safety information, including Boxed WARNINGS. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP "NPOH BMM QMBDFCP DPOUSPMMFE TUVEJFT BCEPNJOBM QBJO WT BOE FEFNB WT XFSF SFQPSUFE NPSF GSFRVFOUMZ JO QBUJFOUT SFDFJWJOH "SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOE FEFNB WT JO UIF "SBOFTQ USFBUFE QBUJFOUT compared to those receiving placebo. 1PTUNBSLFUJOH &YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZ PS FTUBCMJTI B DBVTBM SFMBUJPOTIJQ UP ESVH FYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVT BMMFSHJD SFBDUJPOT Immunogenicity "T XJUI BMM UIFSBQFVUJD QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ /FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS &4"T DBO SFTVMU JO 13$" PS TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT *O DMJOJDBM TUVEJFT UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFE VTJOH UIF #JBDPSF┬о BTTBZ 4FSB GSPN QBUJFOUT XJUI $,% BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO QBUJFOUT XJUI $,% BOE DBODFS QBUJFOUT %VSJOH "SBOFTQ UIFSBQZ SBOHF UP XFFLT B GPMMPX VQ TBNQMF XBT UBLFO 0OF BEEJUJPOBM QBUJFOU XJUI $,% BOE BEEJUJPOBM DBODFS QBUJFOUT EFWFMPQFE BOUJCPEJFT DBQBCMF PG CJOEJOH "SBOFTQ /POF PG UIF QBUJFOUT IBE BOUJCPEJFT DBQBCMF PG OFVUSBMJ[JOH UIF BDUJWJUZ PG "SBOFTQ PS FOEPHFOPVT FSZUISPQPJFUJO BU CBTFMJOF PS BU FOE PG TUVEZ /P DMJOJDBM TFRVFMBF DPOTJTUFOU XJUI 13$" XFSF BTTPDJBUFE XJUI UIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZ PG UIF BTTBZ "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

Aranesp overdosage can cause hemoglobin levels above the desired level, which TIPVME CF NBOBHFE XJUI EJTDPOUJOVBUJPO PS SFEVDUJPO PG "SBOFTQ EPTBHF BOE PS XJUI QIMFCPUPNZ BT DMJOJDBMMZ JOEJDBUFE $BTFT PG TFWFSF IZQFSUFOTJPO IBWF CFFO PCTFSWFE GPMMPXJOH PWFSEPTF XJUI &4"T

Aranesp Placebo Aranesp Placebo O O O O

i$FSFCSPWBTDVMBS EJTPSEFSTw FODPNQBTTFT $F/4 IFNPSSIBHFT BOE DFSFCSPWBTDVMBS BDDJEFOUT JTDIFNJD BOE IFNPSSIBHJD &WFOUT JO UIJT DBUFHPSZ NBZ BMTP CF JODMVEFE VOEFS iUISPNCPFNCPMJD BEWFSTF SFBDUJPOT w

Aranesp┬о EBSCFQPFUJO BMGB

Manufactured by: "NHFO .BOVGBDUVSJOH -JNJUFE B TVCTJEJBSZ PG "NHFO *OD 0OF "NHFO $FOUFS %SJWF 5IPVTBOE 0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF 6 4 1BUFOUT JODMVEJOH 6 4 1BUFOU /P ┬к "NHFO *OD "MM SJHIUT SFTFSWFE 3 7

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2013

2013 Oncology Meetings continued from page 102

July WIN 2013 Symposium: Personalized Cancer Therapy: From Innovation to Implementation July 10-12 • Paris, France For more information: www.winsymposium.org Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

August T:14”

B:14.25”

S:13”

Best of ASCO® Chicago August 9-10 • Chicago, Illinois For more information: boa.asco.org Best of ASCO® Los Angeles August 16-17 • Los Angeles, California For more information: boa.asco.org ISEH – Society for Hematology and Stem Cells 42nd Annual Scientific Meeting August 22-25 • Vienna, Austria For more information: www.iseh.org/?2013Vienna Best of ASCO® Boston August 23-24 • Boston, Massachusetts For more information: boa.asco.org 11th Annual Meeting of Japanese Society of Medical Oncology August 29-31 • Sendai, Japan For more information: www.congre.co.jp/jsmo2013/

Breast Cancer Symposium 2013 September 7-9 • San Francisco, California For more information: www.breastcasym.org

ASTRO 55th Annual Meeting September 22-25 • Atlanta, Georgia For more information: www.astro.org/annualmeeting13 Comprehensive Board Review in Hematology and Medical Oncology September 23-28 • Houston, Texas For more information: www.mdanderson.org/conferences Cancer Survivorship Conference September 27-28 • Houston, Texas For more information: www.mdanderson.org/conferences ECCO-ESMO-ESTRO European Cancer Congress 2013 September 27-October 1 • Amsterdam, The Netherlands For more information: www.ecco-org.eu 28th Annual Offering of Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: from Bench to Bedside to Biomarkers September 30-October 3 • Boston, Massachusetts For more information: steelelab.mgh.harvard.edu/ tumorcourse/

October

September

Symposia on Cancer Research, Genomic Medicine October 4-5 • Houston, Texas For more information: www.mdanderson.org/conferences

SGI Summit Turkey 2013: Innovations in Obstetrics and Gynecology September 6-8 • Istanbul, Turkey For more information: www.sgiturkey2013.org/

9th International Symposium on Hodgkin Lymphoma October 12-15, 2013 • Cologne, Germany For more information: www.hodgkinsymposium.org/

International Clinical Trials Workshop October 17-18 • Santiago, Chile For more information: www.asco.org/ASCOv2/About+ASCO/ International+Affairs/International+Cli nical+Trials+Workshops

Advances in Cancer Survivorship Practice: A Conference for Health Care Professionals October 31-November 1 • Houston, Texas For more information: www.mdanderson.org/conferences

4th International Conference on Stem Cells and Cancer: Proliferation, Differentiation, and Apoptosis October 19-22 • Mumbai, India For more information: www.icscc.in

November

18th International Meeting of the European Society of Gynaecological Oncology October 19-22 • Liverpool, United Kingdom For more information: www2.kenes.com/esgo18 10th International Conference of the Society for Integrative Oncology: Translational Science in Integrative Oncology October 20-22, 2013 • Vancouver, British Columbia For more information: www.integrativeonc.org

Society for Hematopathology/ European Association for Haematopathology 2013 Workshop October 24-26 • Houston, Texas For more information: www.mdanderson.org/conferences 51st Annual Meeting of the Japan Society of Clinical Oncology October 24-26 • Kyoto, Japan For more information: www2.convention.co.jp/jsco2013/ 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org

Quality Care Symposium November 1-2 • San Diego, California For more information: quality.asco.org EMBL Conference on Cancer Genomics November 3-5 • Heidelberg, Germany For more information: www.embl.de 9th NCRI Cancer Conference November 3-6 • Liverpool, United Kingdom For more information: www.ncri.org.uk/ncriconference/ International Clinical Trials Workshop November 7-9 • Santiago, Chile For more information: www.asco.org/ictw Best of ASTRO: Science of Today, Hope for Tomorrow November 8-9 • San Diego, California For more information: www.astro.org/bestofastro African Organization for Research & Training in Cancer 9th International Conference: Cancer in Africa: Bridging Science and Humanity November 21-24 • Durban, South Africa For more information: www.aortic2013.org

December 55th ASH Annual Meeting December 7-10 • New Orleans, Louisiana For more information: www.hematology.org 36th Annual San Antonio Breast Cancer Symposium December 10-14 • San Antonio, Texas For more information: www.sabcs.org

The ASCO Post | MARCH 15, 2013

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ASCO State Affiliates Focus on the Medical Oncology Association of Southern California By Jo Cavallo

Health-care Policy Legislation

Robert A. Moss, MD, FACP

or more than 2 decades, the guiding principle of the Medical Oncology Association of Southern California (MOASC) has been to ensure the continuation of the private practice of medical oncology and to provide the highest quality care to cancer patients. Founded in 1990, MOASC is the largest oncology society in the region and has approximately 300 members. For the past 7 years, Robert A. Moss, MD, FACP, has been MOASC’s President and has overseen the design and implementation of several initiatives to rein in health-care costs throughout California and maintain adequate reimbursement rates for community oncology practices. The ASCO Post talked with Dr. Moss about the unique challenges his society faces and how it plans to meet them.

Is MOASC active in health-care policy legislation? We partner with the Association of Northern California Oncologists and share a legislative lobbyist who gives us monthly updates on any relevant state legislation as well as information on budgetary issues that might affect us. For example, several years ago, thenGovernor Arnold Schwarzenegger proposed an expansion of Medi-Cal (the state’s Medicaid health-care program) that called for a 2% revenue tax on physicians to help fund it. The theory was that because Medi-Cal would be expanded, physicians would benefit from having more patients through the Medi-Cal system. We met with the Governor’s Senior Health Policy Advisor, Herbert Schultz, and explained that a revenue tax on oncologists would affect us disproportionally because so much of our revenue is based on drug costs, where we make very little profit. We also explained that that type of tax would pose an undue burden and result in many community practices closing their doors. We made the point that because many Medi-Cal beneficiaries receive their health care through managed care plans, many oncologists not in the Medi-Cal physician network would be paying the extra tax but not have access to those patients in the managed care

plans. The proposal was eventually scrapped, and we like to feel that we contributed to its demise. The interesting thing about the conversation we had with Mr. Schultz was that I realized that many public policy decision-makers aren’t aware of what takes place in physicians’ offices and how policies like this can so adversely affect the practice of medicine. It was an eyeopener for me, and now I realize how important it is to make your voice heard and educate legislators about what is really happening in the health-care trenches.

MOASC on Physician-assisted Suicide

■■ MOASC is the largest oncology society in the region and has

A legislative accomplishment we had more recently was the defeat of the physician-assisted suicide bill, which has come up in California several years in a row. I am particularly against physician-assisted suicide, as are my board members, and MOASC has come out against the bill each year. Last year, the bill was modified and the physician-assisted suicide provision was removed. The new provision calls for physicians to provide hospice and palliative care information to patients with less than 6 months to live. The bill passed, and we hope that it will neutralize the issue of physician-assisted suicide in the future.

■■ The mission of MOASC is to be a leading oncology society that advances

MOASC Networks

Fast Facts about MOASC ■■ The Medical Oncology Association of Southern California (MOASC) was founded in 1990.

approximately 300 members.

and protects the ability of cancer patients to obtain, and the ability of oncology physicians to provide, optimal cancer care.

■■ MOASC keeps members informed about legislative goals, strategies on

managing clinical practices (including billing and coding changes), and educational seminars through its weekly newsletter, California Oncology Weekly, monthly webinars, bimonthly meetings, certification courses, and practice management consulting seminars.

■■ The Society holds bimonthly board meetings,

bimonthly executive committee meetings, and general membership meetings twice a year.

■■ MOASC members are represented on both ASCO’s

Clinical Practice Committee and ASCO’s State Affiliate Council.

■■ For more information on MOASC, visit www.moasc.org.

One of your major undertakings in 2012 was the creation of the MOASC Contracting Network. What is the purpose of that entity? A few years ago, California was very hard hit by reductions in reimbursements by managed care health insurers, and many oncologists dropped Blue Cross—our biggest insurance payor— because it pays so little. We needed to come up with a way to solve the problem and negotiate reasonable reimbursement rates with the health insurers and find innovative ways to remove unnecessary costs. We decided to partner with

P4, a division of Cardinal Healthcare, which creates payor and provider collaborations to realize both cost-effective and better quality patient care. The idea is that we will develop our own clinical pathways and agree to stick to them about 80% of the time in exchange for insurers giving us an add-on on evaluation and management (E/M) codes. We did not ask for an increase in drug revenues as long as we were adequately reimbursed for the actual services we provide, to be able to maintain high-quality patient care. We are in the process of developing those pathways now. We have established four areas for clinical pathways, including cancers of the breast, lung, and colon, and supportive care. We are now in active contract negotiations with several insurance companies. So far, we have 176 members signed on to the MOASC Contracting Network program. Several years ago, we established the MOASC Purchasing Network, a nonprofit mutual benefit corporation, to help members by negotiating oncology drug prices as well as purchase supplies and equipment directly from manufacturers, distributors, retailers, and wholesalers. We’ve had about 200 members become part of that. We feel it’s a very good deal for our members because they get reduced prices on drugs through a group rate.

Making Practices More Viable These efforts are all meant to support community oncologists in California? Yes, we want to keep the office doors open throughout the state. We’ve had group practices bought out by large hospitals and seen several oncology practices close because of poor reimbursement. As a result, physicians are leaving the state. The only way to prevent that is to make community practices more viable. n

Disclosure: Dr. Moss is President of the Medical Oncology Association of Southern California.

NOW ENROLLING TWO PHASE III STUDIES

BELLE-2 and BELLE-3 Two Phase III studies investigating the pan-PI3K inhibitor, buparlisib (BKM120), plus fulvestrant in HR+/HER2– advanced breast cancer BELLE-2 and BELLE-3 1 Postmenopausal women with HR+/HER2– locally advanced or metastatic breast cancer pretreated with aromatase inhibitor Archival tumor tissue for analysis of PI3K pathway activation No more than one prior line of chemotherapy for metastatic disease ECOG Performance Status ≤2

Randomization

BELLE-3 1

Buparlisib + fulvestrant

Evidence of progression on or after mTOR inhibitor-based treatment

Placebo + fulvestrant

Primary endpoint: Progression-free survival Key secondary endpoint: Overall survival

Buparlisib (BKM120) is an investigational new drug. Efficacy and safety have not been established. There is no guarantee that buparlisib will become commercially available. Additional inclusion/exclusion criteria apply.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase. For more information www.clinicaltrials.gov (NCT01610284 and NCT01633060) Novartis Oncology Clinical Trials Hotline: 1-800-340-6843 (USA only) Or contact your local Novartis representative

Pioneering Research of PI3K inhibitors in Malignancies

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936

Novartis 2012

August 2012

G-BKE-1047878

Novartis Pharma AG CH-4002, Basel, Switzerland

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Journal Spotlight Quality of Care

Study Shows Little Association of Multidisciplinary Tumor Boards with Measures of Care By Matthew Stenger

survey of Veterans Affairs (VA) medical centers recently reported by Nancy L. Keating, MD, MPH, and colleagues at Harvard Medical School in the Journal of the National Cancer Institute showed that the presence of multidisciplinary tumor boards had little association with rates of recommended stage-specific cancer care, differences in use of care, or survival among veterans with colorectal, lung, prostate, or hematologic cancer.1

Study Details In the study, 138 VA medical centers were surveyed for the presence of tumor boards and linked cancer registry and administrative data to assess receipt of stage-specific recommended care, use of care, and survival in patients with cancers diagnosed between 2001 and 2004 and followed through 2005. Of the centers, 35 (25%) had no tumor board, 62 (45%) had a single tumor board, and 41 (30%) had more than one board. In centers with a single board, nearly all discussed all of the cancer types, including lung (97%), colorectal (92%), prostate (92%), breast (85%), and hematologic (84%) cancers. Of the centers with more than one board, 100% had a board specific for lung cancer, 95% for colorectal cancer, 83% for prostate cancer, 73% for hematologic cancer, and 66% for breast cancer. Overall, 27 measures of quality, use, or survival were assessed in the categories of colorectal cancer (4 measures),

Colorectal Cancer For colorectal cancer, comparison across centers with no tumor board, a single general tumor board, and a colorectal cancer–specific tumor board showed no significant differences in measures of adjuvant chemotherapy for stage III colon cancer (68.7%, 69.3%, and 70.4% of patients) or adjuvant chemotherapy and radiation for stage II/III rectal cancer (74.6%, 73.9%, and 74.6%). Likewise, no significant differences were seen in 3-year all-cause survival in patients with colon cancer (survival of 57.5%, 58.2%, and 60.2%) or patients with rectal cancer (survival of 52.5%, 56.2%, and 54.6%).

Lung Cancer For lung cancer, comparison across centers with no tumor board, a general tumor board, and a lung cancer–specific tumor board showed no significant differences in the measures of curative surgery for stage I/II non–small cell lung cancer (NSCLC) (53.2%, 56.5%, and 61.9% of patients), mediastinal evaluation for stage I/II NSCLC (85.7%, 85.6%, and 89.3%), chemotherapy or radiation therapy for stage IIIA NSCLC patients undergoing surgery (79.6%, 74.8%, and 65.1%), or doublet chemotherapy for stage IV lung cancer (37.3%, 42.7%, and 42.8%; no chemotherapy in 56.0%, 52.3%, and 50.6%). However, some significant differences were observed. Radiation ther-

Impact of Tumor Boards ■■ Significant differences among centers with no tumor board, a general

tumor board, or a disease-specific tumor board were observed for 0 of 4 measures of care in colorectal cancer, 3 of 9 measures in lung cancer, 1 of 5 measures in prostate cancer, 2 of 4 measures in hematologic cancer, and 1 of 5 measures in palliative care.

■■ After correction for multiple comparisons, only 1 of 27 measures was significantly associated with the presence of a tumor board.

lung cancer (9 measures), prostate cancer (5 measures), lymphoma/multiple myeloma (4 measures), and palliative and end-of-life care (5 measures). The number of patients with breast cancer was too small to accurately assess measures.

apy in patients with stage I/II NSCLC not undergoing curative surgery was more likely in patients treated at centers with a general tumor board than in patients at a center with no tumor board or a lung cancer–specific tumor board (70.8% vs 66.5% and 63.8%;

EXPERT POINT OF VIEW By Nancy L. Keating, MD, MPH

n this large study examining care for patients with a variety of tumor types in the Veterans Health Administration (VA), we found no clear association of tumor boards with better quality of care or outcomes. It is unclear if our findings can be generalized outside of the VA, although in other work, we have shown that the quality of care for patients with cancer in this setting is similar to or better than that with fee-for-service Medicare. Most likely, any impact of tumor boards on quality Nancy L. Keating, MD, MPH depends on the tumor board participants and the role of the tumor board. In addition, it is possible that tumor boards may provide limited additional benefit when performance is assessed using generally accepted measures of guideline-recommended care, as was the case in our study, but they may be particularly helpful for patients for whom treatment decisions are more complex. Nevertheless, it remains true that very little is known about the structure and function of tumor boards and the outcomes associated with their use, despite the large number of person hours that are required for tumor boards to function. n Disclosure: Dr. Keating reported no potential conflicts of interest.

Dr. Keating is Associate Professor of Medicine and of Health Care Policy at Harvard Medical School and Associate Physician at Brigham and Women’s Hospital, Boston.

overall P = .04). Chemotherapy and radiation therapy for unresected NSCLC stage IIIA patients was more likely in patients from centers with a general tumor board or a cancerspecific board than in patients from centers with no tumor board (39.5% and 35.6% vs 23.9%; overall P = .02). Treatment at a center with a general board or a cancer-specific board was associated with a greater likelihood of chemotherapy and radiation therapy for limited-stage small cell lung cancer (61.8% and 62.9% vs 28.4%; overall P < .001). Comparison across centers with no tumor board, a general tumor board, and a lung cancer–specific tumor board found no significant differences in 1-year all-cause survival in NSCLC (41.3%, 39.5%, and 41.0%) or small cell lung cancer (25.2%, 26.2%, and 26.6%).

Prostate Cancer For prostate cancer, comparison across centers with no tumor board, a general tumor board, and a prostate cancer–specific tumor board showed

no significant differences in the measures of primary therapy for local/ regional prostate cancer (no radiation or surgery in 38.9%, 38.9%, and 37.7% of patients), androgen ablation for metastatic prostate cancer (77.2%, 70.7%, and 76.9%), adjuvant androgen-deprivation therapy for high-risk cancers treated with radiation therapy (2001–2002) (56.7%, 63.0%, and 68.6%), or use of three-dimensional conformal radiation therapy/intensity-modulated radiation therapy for patients receiving external-beam radiation therapy (61.0%, 59.3%, and 61.0%). Patients treated at centers with a general tumor board or a prostate cancer–specific board were significantly more likely to receive an oral antiandrogen before starting gonadotropinreleasing hormone agonist therapy for metastatic disease (81.7% and 83.7% vs 71.1%; overall P = .03).

Lymphoma/Multiple Myeloma For lymphoma/multiple myeloma, comparison across centers with no tucontinued on page 111

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In Memoriam

Zora Brown, Prominent Cancer Research Advocate, Dies at 63

he American Association for Cancer Research (AACR) reported with sadness the loss of Zora Brown, a trustee for the AACR Foundation for the Prevention and Cure of Cancer, a breast and ovarian cancer survivor, and a pioneering advocate for cancer research and breast cancer awareness among minorities. Ms. Brown, who passed away March 3, 2013, at 63 years of age, was also the founder and chairperson of Cancer Awareness Program Services (CAPS) and the Breast Cancer Resource Committee (BCRC), an organization dedicated to lowering the breast cancer mortality rate among African-Americans.

“There is a hole in our hearts as we mourn the loss of Zora Brown, who despite her many years of dealing with two cancers and multiple relapses, maintained an amazing and courageous spirit that inspired everyone around her,” said Margaret Foti, PhD, MD (h.c.), AACR’s Chief Executive Officer. “Her life’s work as a cancer advocate has been extremely important in increasing public awareness about cancer, especially among women. In her memory and honor, we will do our utmost to work even harder to expedite the prevention and cure of this disease that takes so many.”

[Zora Brown’s] life’s work as a cancer advocate has been extremely important in increasing public awareness about cancer, especially among women. In her memory and honor, we will do our utmost to work even harder to expedite the prevention and cure of this disease that takes so many. —Margaret Foti, PhD, MD (h.c.)

Advocate for All Women At the end of her life, Ms. Brown was living with stage III ovarian cancer, but she was first diagnosed with breast cancer in 1981, at just 32, and then again in 1997. Her experience with cancer led her to devote her life as an advocate for women, and for African-American women in particular, with breast and ovarian cancers.

Presidential-appointed Member of NCAB

Zora Brown (left) and Margaret Foti, PhD, MD (h.c.)

Tumor Boards continued from page 110

mor board, a general tumor board, and a hematology-specific tumor board showed no significant differences in the measures of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy in diffuse large B-cell non-Hodgkin lymphoma (NHL) (80.7%, 75.4%, and 80.6% of patients) or bisphosphonate therapy for multiple myeloma (59.6%, 66.4%, and 66.2%). Treatment with rituximab and CHOP in patients with diffuse large Bcell NHL was significantly less likely at centers with a general tumor board than at those with no tumor board or a hematology-specific tumor board (74.6% vs 89.3% and 87.1%; overall P = .003). White blood cell growth factor treatment with CHOP in patients with diffuse large B-cell NHL was less likely

at a center with a hematology-specific board than at centers with no tumor board or a general tumor board (39.4% vs 56.4% and 61.3%; overall P = .002).

Palliative Care Palliative care specialists were included in only 31% of tumor boards. For palliative care and end-of-life care, comparison across centers with no tumor board, a tumor board without palliative care specialists, and a tumor board with specialists showed no significant differences in the measures of receipt of last dose of chemotherapy within 14 days of death (4.8%, 5.8%, and 5.4%), intensive care unit admission within 30 days of death (15.7%, 12.8%, and 13.1%), use of potent antiemetics for highly emetogenic chemotherapy (64.7%, 75.4%, and 66.4%; overall P = .10), or prescription of narcotic pain med-

In 1991, President Bush appointed Ms. Brown to the National Cancer Advisory Board (NCAB) to serve on the 18-member advisory body of outside experts whose primary task is to advise the secretary of Health and Human Services, the director of the National Cancer Institute (NCI), and ultimately the president of the United States on a range of issues affecting the nation’s cancer program ication for pain in advanced cancer (69.6%, 68.6%, and 67.0%). Patients treated at centers with a tumor board that did not include a palliative care specialist were more likely to have more than one emergency room visit within 30 days of death than patients treated at centers with no tumor board or with a tumor board including a palliative care specialist (12.0% vs 9.6% and 9.2%; overall P = .01). After a Bonferroni correction for multiple comparisons, the only association that remained significant among all 27 measures included in the analysis was the greater likelihood of use of chemotherapy and radiation therapy for limited-stage small cell lung cancer at centers with a general tumor board or a lung cancer–specific tumor board. The authors concluded, “We ob-

and, specifically, NCI operations. She served on the board until 1998. Due in part to Ms. Brown’s influence, Congress appropriated $500,000 for breast and cervical screening for low-income, uninsured, inner-city women. “The AACR and cancer research community lost an amazing and gracious woman with the passing of Zora Brown. I cannot stress enough the importance of her work as an advocate for cancer research. She, along with other advocates, are the unsung heroes in fight against cancer,” said AACR President Frank McCormick, Ph.D., director of the UCSF Helen Diller Family Comprehensive Cancer Center. “Zora’s strength in battling her cancers and her passion for advocating for women with cancer were an inspiration to us all. She will be dearly missed but certainly never forgotten.” n served little association of multidisciplinary tumor boards with measures of use, quality, or survival. This could mean that tumor boards did not, in fact, influence quality of cancer care in the VA setting. It might also mean that tumor boards are only as good as their structural and functional components and the expertise of the participants, and because tumor boards likely vary in their efficacy depending on these factors, measuring only the presence of a tumor board may not be sufficient to understand their effects. Additional research is needed to understand the structure and format of tumor boards that lead to the highest quality care.” n Reference 1. Keating NL, Landrum MB, Lamont EB, et al: Tumor boards and the quality of cancer care. J Natl Cancer Inst 105:113121, 2013.

MULTIPLE MYELOMA IS

RELENTLESS . YOUR DEDICATION IS

ENDLESS. In honor of Multiple Myeloma Awareness Month, Celgene would like to express our gratitude to all the physicians, nurses, researchers, and advocates who are always focused on improving the lives of patients with this disease. Working together, we are as relentless, persistent, and progressive as multiple myeloma. And weâ&#x20AC;&#x2122;re not done yet.

ÂŠ 2013 Celgene Corporation

02/13

US-CELG130012a

www.celgene.com

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Patient’s Corner Breast Cancer

My Life Will Never Be Normal

I thought I could go through breast cancer treatment, and afterward my life would return to the way it was before. That’s not what happened. By Susan Zager, as told to Jo Cavallo

T:14”

B:14.25”

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fter being diagnosed with stage II invasive ductal carcinoma in my right breast in 2004, I did an Internet search to learn more about my treatment options so I could be prepared when I met with my oncologist to discuss my treatment plan. I was especially interested in therapies that would be effective but allow me to salvage my hair. Despite my efforts, however, in addition to a lumpectomy, my oncologist was recommending the standard course of therapy for my type of cancer, including four cycles of a highdose combination of doxorubicin and cyclophosphamide, followed by four cycles of paclitaxel, plus 35 days of radiation therapy over 7 weeks. With this regimen, I knew my hair didn’t have a chance. What I didn’t expect to see was all my toenails floating to the top of the water one night while I was taking a bath. Although I didn’t feel any pain, the sight of my toes without nails and my head without hair made me truly sad. I know that the point of all this treatment was to make me well, but I couldn’t help but feel that one by one, I was losing parts of my life that made me who I am. The cumulative side effects from my treatment, including fatigue, nonstop vomiting, weight loss, and “chemobrain” were overwhelming. And because I was so sick and weak from all the chemotherapy, I couldn’t take adjuvant tamoxifen therapy.

Problems of Reconstructive Surgery I have wondered if skipping tamoxifen may have contributed to a local breast cancer recurrence a year-anda-half later, but I have friends who are ER-positive and have had distant metastatic recurrences. I’ll never know for sure if tamoxifen would have made a difference, but the ensuing physical changes I’ve experienced since my recurrence guarantees that my body and

Visit

my life will never be the same. The new cancerous mass was small and confined to my right breast. I decided to have a bilateral mastectomy to avoid the possibility that I might develop cancer in my left breast as well. It had only been 15 months since I ended treatment, and I believed my body was determined to have more breast cancer. The bilateral mastectomy sparing the left nipple made the most sense with my set of circumstances. I have no regrets about that decision. Since I had had radiation therapy

of the potential complications of using implants to reconstruct my breasts, even though I had asked if the type of surgery I chose made a difference.

Living My Best Life The cumulative effects from all the drugs and surgeries over the past 8 years have taken a toll. And a hip break due to osteoporosis, a late effect from my treatment, has added another scar to my already tattered body. However, I maintain a regular exercise routine and have worked hard to restore my

Despite my concerns, I’m happy to be alive and I try to live life to the fullest. I have become a patient advocate for breast cancer survivors and find great satisfaction in helping others become better educated about their disease and more proactive in their care. —Susan Zager

and subsequent skin damage, there were problems using implants for my breast reconstruction. After several failed reconstruction attempts including a lateral flap, I found a fantastic plastic surgeon who was able to do various things surgically and give me a beautiful aesthetic result. Nevertheless, the reconstructed breasts are hard to the touch and do not feel natural. Women contemplating a contralateral prophylactic mastectomy need to be aware that no matter how skilled the plastic surgeon, reconstructed breasts are not the same as natural breasts. They also need to know the complications that can arise as a result of radiation-related skin damage and be given advice on which type of reconstruction surgery has the best chance of success. I’m disappointed because my oncology surgeon never told me

strength. I am so happy that the chemobrain faded away, and I feel that my mind and memory are in top form again. More than the physical effects of having breast cancer, I worry about the statistic showing that 30% of early-stage breast cancer survivors eventually develop distant recurrence and stage IV disease, especially because my best friend—who had chemotherapy for pri-

mary breast cancer at the same time as me—was in the 30% and died of metastatic breast cancer. I have many friends with metastatic breast cancer, and I am determined that they be helped. While I am thrilled that I currently have no evidence of disease, I am concerned that those with metastatic breast cancer have sometimes been lost in the sea of pink survivors. I was prescribed tamoxifen after my cancer recurred 5 years ago (and have tolerated the drug), but I live with the knowledge that my cancer could eventually become metastatic. Despite my concerns, I’m happy to be alive and I try to live life to the fullest. I have become a patient advocate for breast cancer survivors and find great satisfaction in helping others become better educated about their disease and more proactive in their care. I have been to two major Breast Cancer Symposiums and the San Antonio Breast Cancer Symposium, among other professional meetings. I am delighted that the oncology community is interested in patient advocates’ insights, recognizing how educated patient advocates can be and how much we have to offer. While I keep vigilant for any new signs of health problems, I never forget to take pleasure in the ordinariness of every day. n Susan Zager is the founder of Advocates for Breast Cancer and lives in Los Angeles, California.

Patient Information Available at Cancer.Net

ancer.Net offers information written for patients on breast reconstruction and what to expect following a mastectomy. To obtain this information, you may wish to recommend your patients visit http://www.cancer.net/ cancer-types/breast-cancer/treatment. Also, to learn more about ASCO programs for patient advocates, visit http://www.cancer.net/advocacy-and-policy/patient-advocacy-and-asco. n

website at ASCOPost.com

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Integrative Oncology Fitness: Can Exercise Lengthen Survival in Patients with Cancer? By Barrie R. Cassileth, MS, PhD, Ian Yarett, and Dawn Lemanne, MD, MPH Integrative Medicine Service Memorial Sloan-Kettering Cancer Center, New York

egular physical activity has long been associated with decreased risk of disease, including many types of cancer. Such benefits may translate into increased life expectancy of up to 4.5 years, with even the lowest levels of activity providing some survival advantage.1 Most strikingly, however, evidence from the past several years suggests that physical activity is not only safe in patients already diagnosed with cancer, but also that it may decrease the risk of recurrence and extend survival. This overview presents a summary of the research to date and its clinical implications for cancer care providers. The effects of postdiagnosis physical activity on cancer recurrence and survival have been examined in over 20 observational studies but in few randomized controlled trials.2 Existing studies have focused primarily on breast, colorectal, prostate, and ovarian cancer survivors. They generally describe an inverse relationship between level of postdiagnosis physical activity and risk of cancer recurrence and/or mortality, with the strongest evidence found in patients with breast and colorectal cancer.

Breast Cancer Research suggests that patients with breast cancer who engage in moderate physical activity at various levels have a significantly lower risk of

cancer-specific and/or all-cause mortality. The safety of physical activity in breast cancer survivors, even during treatment, has been documented in numerous trials.2 One prospective observational study of 933 women with local or regional breast cancer found that any moderate intensity exercise after diagnosis, such as brisk walking, reduced mortality risk by 64% compared to inactive women.3 Exercise of the same intensity for 2.5 hr/wk—the level recommended for the general population by the U.S. Department of Health and Human services4—was associated with a mortality reduction of 67% compared to inactive women.3 Generally, a decreased risk of 40% to 67% was observed across studies.3,5,6 A recent meta-analysis of six studies, covering 12,108 patients, found that postdiagnosis exercise was associated with a 34% lower risk of breast cancerrelated deaths, a 41% lower risk of allcause mortality, and a 24% lower risk of breast cancer recurrence.7

Colorectal Cancer Several large cohort studies in colorectal cancer survivors document similar survival advantages and reduced recurrence risk in patients who engaged in physical activity after diagnosis, with improvements of up to 50%.8-11 Based on the promise of these findings, a phase�� III�� randomized con-

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, Barrie R. Cassileth, MS, PhD minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 265 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan-Kettering Cancer Center’s very first mobile application, was launched last fall. In the week following its release on September 21, the app was downloaded more than 6,300 times, making it #4 on the top new medical apps chart. The app is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http:// itunes.apple.com/us/app/about-herbs/id554267162?mt=8. trolled trial called the Colon Health and Life-Long Exercise Change trial (CHALLENGE) is now underway to assess the effects of a 3-year physical activity program on clinical outcomes in stage�� II and III colon cancer survivors who have completed chemotherapy.12

Mechanisms Underlying the Survival Benefits Despite evidence that physical activity may extend survival, the specific biologic mechanisms that underlie this

benefit remain unclear. With regard to breast cancer, exercise is postulated to affect survival by decreasing body fat, insulin resistance, sex hormone levels and inflammation, all of which would be expected to improve cancer-specific survival.13 Women who are overweight, obese, or have high fasting insulin levels at time of diagnosis, or who gain weight after diagnosis, tend to have poorer outcomes.14-16 Thus, weight loss facilitated by physical activity may improve cancer-specific survival.

Learn More About

Herbs, Botanicals, & Other Products Visit the About Herbs website at

www.mskcc.org/aboutherbs

continued on page 119

XGEVA速 (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA速 is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. Please see the following pages for Important Safety Information.

XGEVA®, THE FIRST AND ONLY RANK LIGAND INHIBITOR TO PREVENT SREs

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

• Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

www.XGEVA.com

SUPERIORITY XGEVA® delayed the median time to ﬁrst SRE in a prespeciﬁed integrated analysis across 3 head-to-head studies vs zoledronic acid1

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients1,2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

HR = 0.83 (95% CI: 0.76–0.90) P < 0.0001†

0 0

Reduction in risk of ﬁrst SRE in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)3 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)3 • Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)3 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

STUDY MONTH Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.3

SUBCUTANEOUS INJECTION

NO DOSE ADJUSTMENTS

PRECISE ACTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function3-8

XGEVA® acts precisely to bind XGEVA® is administered once to RANK Ligand, a key mediator every 4 weeks as a single, 120 mg of bone resorption, to inhibit subcutaneous injection3 osteoclast activity3

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.3

Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identiﬁed.

Please see brief summary of Prescribing Information on the following page.

REFERENCES: 1. Lipton A, Siena S, Rader M, et al. Comparison of denosumab versus zoledronic acid for treatment of bone metastases in advanced cancer patients: an integrated analysis of 3 pivotal trials. Ann Oncol. 2010;21(suppl 8):viii380. Abstract 1249P and poster. 2. Data on ﬁle, Amgen. 3. XGEVA® (denosumab) prescribing information, Amgen. 4. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 5. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 6. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507. 7. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39. 8. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

T:9.5â&#x20AC;?

Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients developed ONJ after a median exposure of 20 doses. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should immunogenicity. Using an electrochemiluminescent bridging immunoassay, less receive care by a dentist or an oral surgeon. In these patients, extensive dental than 1% (7/2758) of patients with osseous metastases treated with denosumab surgery to treat ONJ may exacerbate the condition. doses ranging from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant 3 years tested positive for binding antibodies. No patient with positive binding woman. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse antibodies tested positive for neutralizing antibodies as assessed using a reproductive effects. In utero denosumab exposure in cynomolgus monkeys chemiluminescent cell-based in vitro biological assay. There was no evidence resulted in increased fetal loss, stillbirths, and postnatal mortality, along with of altered pharmacokinetic proďŹ le, toxicity proďŹ le, or clinical response associated evidence of absent peripheral lymph nodes, abnormal bone growth and with binding antibody development. The incidence of antibody formation is decreased neonatal growth (see Use in SpeciďŹ c Populations). There are no highly dependent on the sensitivity and speciďŹ city of the assay. Additionally, adequate and well controlled studies with Xgeva in pregnant women. Women the observed incidence of a positive antibody (including neutralizing antibody) should be advised not to become pregnant when taking Xgeva. If this drug is test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, used during pregnancy, or if the patient becomes pregnant while taking this drug, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab the patient should be apprised of the potential hazard to the fetus. with the incidence of antibodies to other products may be misleading. ADVERSE REACTIONS: The following adverse reactions are discussed below DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted and elsewhere in the labeling: with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva t )ZQPDBMDFNJB TFF 8BSOJOHT BOE 1SFDBVUJPOT

was administered in combination with standard anticancer treatment. Serum t 0TUFPOFDSPTJT PG UIF +BX TFF 8BSOJOHT BOE 1SFDBVUJPOT) denosumab concentrations at 1 and 3 months and reductions in the bone turnover The most common adverse reactions in patients receiving Xgeva (per-patient marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, were similar in patients with and without prior intravenous bisphosphonate therapy. and nausea (see Table 1). The most common serious adverse reaction in patients There was no evidence that various anticancer treatments affected denosumab receiving Xgeva was dyspnea. The most common adverse reactions resulting in systemic exposure and pharmacodynamic effect. Serum denosumab concentrations discontinuation of Xgeva were osteonecrosis and hypocalcemia. at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone Clinical Trials Experience. Because clinical trials are conducted under widely therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar varying conditions, adverse reaction rates observed in the clinical trials of a drug between patients receiving concomitant chemotherapy and/or hormone cannot be directly compared to rates in other clinical trials and may not reďŹ&#x201A;ect the therapy (see Clinical Pharmacology [12.2] in full Prescribing Information). rates observed in practice. The safety of Xgeva was evaluated in three randomized, USE IN SPECIFIC POPULATIONS: double-blind, double-dummy trials (see Clinical Trials [14] in full Prescribing Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Information) in which a total of 2841 patients with bone metastasis from prostate Xgeva can cause fetal harm when administered to a pregnant woman based cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple on ďŹ ndings in animals. In utero denosumab exposure in cynomolgus monkeys myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were resulted in increased fetal loss, stillbirths, and postnatal mortality, along with randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid evidence of absent lymph nodes, abnormal bone growth and decreased every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium neonatal growth. There are no adequate and well-controlled studies with Xgeva (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance in pregnant women. Women should be advised not to become pregnant when 30 mL/min or greater. Patients who had received IV bisphosphonates were taking Xgeva. If this drug is used during pregnancy, or if the patient becomes excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an pregnant while taking this drug, the patient should be apprised of the potential active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, hazard to the fetus. Women who become pregnant during Xgeva treatment are or any planned invasive dental procedure. During the study, serum chemistries encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or including calcium and phosphorus were monitored every 4 weeks. Calcium and their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received 9HFWB XFSF GFNBMF &JHIUZ mWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP Asian, and 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). SeventyďŹ ve percent of patients who received Xgeva received concomitant chemotherapy.

DOUS2X0319_T_4Pg Tabloid_Update_Aug_12_BS_r8.indd 1

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in continuing or discontinuing treatment with Xgeva.

Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology [12.3] in full Prescribing Information). OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: t 4ZNQUPNT PG IZQPDBMDFNJB JODMVEJOH QBSFTUIFTJBT PS NVTDMF TUJGGOFTT twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) Advise patients of the need for: t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ÂŠ2012 Amgen Inc. All rights reserved. Printed in USA.

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Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Animal Data: The effects of denosumab on prenatal development have been studied Severity (Trials 1, 2, and 3) in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). Xgeva Zoledronic Acid In cynomolgus monkeys dosed subcutaneously with denosumab throughout Body System n = 2841 n = 2836 pregnancy at a pharmacologically active dose, there was increased fetal loss during % % gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal GASTROINTESTINAL bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and Nausea 31 32 tooth malalignment; and decreased neonatal growth. At birth out to one month of Diarrhea 20 19 age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects GENERAL on bone quality and strength returned to normal; there were no adverse effects Fatigue/ Asthenia 45 46 on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes INVESTIGATIONS were present, though small; and minimal to moderate mineralization in multiple )ZQPDBMDFNJBb 18 9 tissues was seen in one recovery animal. There was no evidence of maternal 32 20 )ZQPQIPTQIBUFNJBb harm prior to labor; adverse maternal effects occurred infrequently during labor. NEUROLOGICAL Maternal mammary gland development was normal. There was no fetal NOAEL (no )FBEBDIF 13 14 observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of RESPIRATORY denosumab) also caused fetal lymph node agenesis and led to postnatal impairment Dyspnea 21 18 of dentition and bone growth. Pregnant RANKL knockout mice showed altered Cough 15 15 maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information). a Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials Nursing Mothers. It is not known whether Xgeva is excreted into human milk. 1, 2, and 3, and meeting one of the following criteria: Measurable concentrations of denosumab were present in the maternal milk t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS of cynomolgus monkeys up to 1 month after the last dose of denosumab t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and 5% greater incidence in patients treated with zoledronic acid compared to because of the potential for serious adverse reactions in nursing infants from placebo (US Prescribing Information for zoledronic acid) Xgeva, a decision should be made whether to discontinue nursing or discontinue b Laboratory-derived and below the central laboratory lower limit of normal the drug, taking into account the importance of the drug to the mother. Maternal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] signaling pathway that have shown altered maturation of the maternal mammary Severe Mineral/Electrolyte Abnormalities HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT monkeys treated with denosumab throughout pregnancy, maternal mammary than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% gland development was normal, with no impaired lactation. Mammary gland of patients treated with zoledronic acid. Of patients who experienced severe histopathology at 6 months of age was normal in female offspring exposed to hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia denosumab in utero; however, development and lactation have not been fully and 16% experienced 3 or more episodes (see Warnings and Precautions and evaluated (see Nonclinical Toxicology [13.2] in Full Prescribing Information). Use in SpeciďŹ c Populations). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO effectiveness of Xgeva in pediatric patients have not been established. Treatment 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of with Xgeva may impair bone growth in children with open growth plates and patients treated with zoledronic acid. may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target Osteonecrosis of the Jaw of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in at doses â&#x2030;¤ 10 mg/kg was associated with inhibition of bone growth and tooth 1.8% of patients in the Xgeva group and 1.3% of patients in the zoledronic eruption. Adolescent primates treated with denosumab at doses 5 and 25 times acid group (see Warnings and Precautions). When events occurring during an (10 and 50 mg/kg dose) higher than the recommended human dose of extended treatment phase of approximately 4 months in each trial are included, 120 mg administered once every 4 weeks, based on body weight (mg/kg), had the incidence of conďŹ rmed ONJ was 2.2% in patients who received Xgeva. The abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, Postmarketing Experience. Because postmarketing reactions are reported decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and voluntarily from a population of uncertain size, it is not always possible to reliably mesenteric lymph nodes. Some bone abnormalities recovered once exposure estimate their frequency or establish a causal relationship to drug exposure. was ceased following birth; however, axillary and inguinal lymph nodes remained The following adverse reactions have been identiďŹ ed during post approval absent 6 months post-birth (see Use in Pregnancy). use of Xgeva: Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. were 65 years of age or older. No overall differences in safety or efďŹ cacy were Immunogenicity. As with all therapeutic proteins, there is potential for observed between these patients and younger patients.

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Integrative Oncology Can Exercise Lengthen Survival? continued from page 114

A study published in JAMA in 2005 found that the amount of exercise was associated with increased survival in a dose-dependent fashion. These investigators also noted that the survival advantage from physical activity was greater for women with estrogen receptor–positive tumors.6 Because drugs that decrease estrogen activity, such as tamoxifen and aromatase inhibitors, help treat hormone-sensitive tumors, exerciseinduced decreases in sex hormone signaling might have similar benefits. Exercise also may modulate inflammatory signaling, which in turn is postulated to have a role in tumor angiogenesis and metastasis. A recent study in mice using human breast cancer xenografts demonstrated that increased inflammatory signaling in tumor-associated endothelial tissue accelerated tumor growth and, further, that disruption of this signaling impaired growth.17

Moderate-intensity vs High-intensity Exercise Exercise research in patients with cancer has focused on moderateintensity exercise, which requires exertion at 60% to 75% of maximal effort. High-intensity aerobic exercise, however, which involves 10- to 30-second sprints at or near maximal effort, may reduce body fat, improve insulin resistance, and modulate inflammation more quickly and effectively than moderate exercise.18-21 In addition, high-intensity exercise improves motivation and adherence in participants.22,23 An ongoing study at Memorial Sloan-Kettering Cancer Center will assess the safety and feasibility of a high-intensity exercise program in patients with breast cancer and compare the effects of high- vs moderate intensity exercise on relevant biomarkers.

Motivating Patients to Exercise Despite strong evidence supporting the safety and benefits of exercise in cancer survivors, most are not physically active. Studies suggest that fewer than 10% of cancer survivors are physically active during their primary treatments and only 20% to 30% are active after treatment.2 Thus, behavioral support interventions are needed to help

patients with cancer experience the benefits of a physically active lifestyle. Short-term supervised exercise, support groups, and telephone counseling are among the strategies that have been successful.2

Concluding Thoughts Taken together, the available evidence suggests that exercise can help improve cancer-specific survival in patients, although the physiologic mechanisms await documentation. Further research, particularly via randomized controlled trials, is needed to establish the most ef-

Cancer J Clin 62:243-274, 2012. 3. Irwin ML, Smith AW, McTiernan A, et al: Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: The health, eating, activity, and lifestyle study. J Clin Oncol 26:3958-3964, 2008. 4. U.S. Department of Health and Human Services: 2008 Physical Activity Guidelines for Americans. Washington, DC, U.S. Department of Health and Human Services, 2008. 5. Holick CN, Newcomb PA, Trentham-Dietz A, et al: Physical activity and survival after diagnosis of invasive breast

In light of the apparent survival benefit and the many other positive effects of exercise—such as improved physical function, quality of life, and psychological well being—it is advisable for cancer survivors to meet the recommended 2.5 hours per week of moderate exercise to the extent that their physical condition allows. —Barrie R. Cassileth, MS, PhD, Ian Yarrett, and Dawn Lemanne, MD, MPH

fective amount, timing, and type of exercise, as well as whether and how these may vary by specific cancer diagnosis. In light of the apparent survival benefit and the many other positive effects of exercise—such as improved physical function, quality of life, and psychological well being—it is advisable for cancer survivors to meet the recommended 2.5 hours per week of moderate exercise to the extent that their physical condition allows. Care must be taken to avoid exercise-related injuries, mitigate the risk of adverse effects, and consider the patient’s physical condition, treatment regimen, etc. Special precautions should be taken for older adults with bone disease, for example. Survivor-specific guidelines developed by an expert panel of the American College of Sports Medicine may be a useful resource. It recommends that survivors avoid inactivity and become physically active as soon as possible after diagnosis and/or treatment.24 n

Disclosure: Drs. Cassileth and Lemanne and Mr. Yarett reported no potential conflicts of interest.

References 1. Moore SC, Patel AV, Matthews CE, et al: Leisure time physical activity of moderate to vigorous intensity and mortality: A large pooled cohort analysis. PLoS Med 9:e1001335, 2012. 2. Rock CL, Doyle C, Demark-Wahnefried W, et al: Nutrition and physical activity guidelines for cancer survivors. CA

cancer. Cancer Epidemiol Biomarkers Prev 17:379-386, 2008. 6. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:24792486, 2005. 7. Ibrahim EM, Al-Homaidh A: Physical activity and survival after breast cancer diagnosis: Meta-analysis of published studies. Med Oncol 28:753-765, 2011. 8. Meyerhardt JA, Giovannucci EL, Ogino S, et al: Physical activity and male colorectal cancer survival. Arch Intern Med 169:2102-2108, 2009. 9. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al: Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol 24:3535-3541, 2006. 10. Meyerhardt JA, Giovannucci EL, Holmes MD, et al: Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527-3534, 2006. 11. Haydon AM, Macinnis RJ, English DR, et al: Effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut 55:62-67, 2006. 12. Courneya KS, Booth CM, Gill S, et al: The Colon Health and Life-Long Exercise Change trial: A randomized trial of the National Cancer Institute of Canada Clinical Trials Group. Curr Oncol 15:279-285, 2008. 13. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al: Physical activity, biomarkers, and disease outcomes in can-

cer survivors: A systematic review. J Natl Cancer Inst 104:815-840, 2012. 14. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20:4251, 2002. 15. Bradshaw PT, Ibrahim JG, Stevens J, et al: Postdiagnosis change in bodyweight and survival after breast cancer diagnosis. Epidemiology 23:3207, 2012. 16. Nichols HB, Trentham-Dietz A, Egan KM, et al: Body mass index before and after breast cancer diagnosis: Associations with all-cause, breast cancer, and cardiovascular disease mortality. Cancer Epidemiol Biomarkers Prev 18:1403-1409, 2009. 17. Pitroda SP, Zhou T, Sweis RF, et al: Tumor endothelial inflammation predicts clinical outcome in diverse human cancers. PLoS One 7:e46104, 2012. 18. King AC, Haskell WL, Young DR, et al: Long-term effects of varying intensities and formats of physical activity on participation rates, fitness, and lipoproteins in men and women aged 50 to 65 years. Circulation 91:2596-2604, 1995. 19. Richards JC, Johnson TK, Kuzma JN, et al: Short-term sprint interval training increases insulin sensitivity in healthy adults but does not affect the thermogenic response to beta-adrenergic stimulation. J Physiol 588:2961-2972, 2010. 20. Leggate M, Carter WG, Evans MJ, et al: Determination of inflammatory and prominent proteomic changes in plasma and adipose tissue after high-intensity intermittent training in overweight and obese males. J Appl Physiol 112:13531360, 2012. 21. Lee MG, Park KS, Kim DU, et al: Effects of high-intensity exercise training on body composition, abdominal fat loss, and cardiorespiratory fitness in middleaged Korean females. Appl Physiol Nutr Metab 37:1019-1027, 2012. 22. Wisloff U, Stoylen A, Loennechen JP, et al: Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: A randomized study. Circulation 115:3086-3094, 2007. 23. Bartlett JD, Close GL, MacLaren DP, et al: High-intensity interval running is perceived to be more enjoyable than moderate-intensity continuous exercise: Implications for exercise adherence. J Sports Sci 29:547-553, 2011. 24. Schmitz KH, Courneya KS, Matthews C, et al: American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 42:1409-1426, 2010.

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Patients with Cancer Need to Know That It Is Never Too Late to Quit Smoking By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

atients with head and neck or lung cancer who quit smoking even the week before surgical treatment are much more likely to remain abstinent from smoking and to reap the benefits of continued abstinence from smoking than are those who wait until after surgery to quit. These benefits—as listed in a study published in the journal Cancer,1 and as reported by health and consumer media—can be immediate, such as increased effi-

cacy of treatment and reduced rates of surgical complications and adverse effects, and long-term, such as reduced risk of cancer recurrence, second primary tumors, heart disease, and other smoking-related illnesses. “Patients with cancer need to know that it is never too late to quit smoking,” noted Vani Nath Simmons, PhD, the study’s corresponding author and Assistant Member in the Health Outcomes and Behavior Department at the H. Lee Moffitt Cancer Center, and Assistant Professor at the University of South Florida in Tampa, Florida. “Regardless of the cancer type or stage, benefits can certainly be seen by quitting smoking and staying quit after cancer treatment,” she said in an interview with The ASCO Post. “Research shows that the outcomes for just about any cancer and any treat-

ment, and the quality of life, regardless of the duration of the life remaining, are higher if patients do in fact quit smoking,” Thomas H. Brandon, PhD, added. A coauthor of the study, Dr. Brandon is Chair of the Health Outcomes and Behavior Department and Director of the Tobacco Research and Intervention Program at Moffitt Cancer Center.

Relapse Rates Vary Significantly A total of 154 patients, recruited from the thoracic and head and neck clinics at Moffitt Cancer Center, participated in the study. All had a history of smoking at least 10 cigarettes per day for at least 1 year before a diagnosis of cancer. All patients were abstinent from smoking for at least 24 hours after surgery; 53 patients had quit smoking

Thomas H. Brandon, PhD and Vani Nath Simmons, PhD

shortly before surgical cancer treatment, and 101 had quit smoking immediately after surgery. Smoking behavior was assessed at 2, 4, 6, and 12 months after surgery. While all patients had access to Moffitt’s certified tobacco cessation specialist, no smoking intervention was provided as part of the study. “Relapse rates varied significantly,

Ask Patients about Their Smoking Status

“R

eceiving a cancer diagnosis represents a ‘teachable moment’ for delivering smoking cessation and relapse prevention interventions,” concluded a study in the journal Cancer1 about smoking relapse in patients with thoracic cancer or head and neck cancer. Previous research by two of the study’s authors, Vani Nath Simmons, PhD, and Thomas H. Brandon, PhD, of the Health Outcomes and Behavior Department at H. Lee Moffitt Cancer Center in Tampa, Florida, and their colleagues at the University of South Florida, showed that oncologists and other health-care professionals may not be fully capitalizing on that teachable moment.

are more acute, immediate effects for cancer patients who continue to smoke,” he said. “For example, patients may have greater risk of treatment complications or their treatment may be less effective. They may have greater side effects or poorer wound healing. Those are just some examples of some of the more immediate consequences that patients face.” A later study asked 81 patients with thoracic cancer and 87 with head and neck cancer to assess whether oncol-

Some providers were very sensitive to the stigma that cancer patients may feel with regard to their smoking, and others may not have as much sensitivity as needed. —Vani Nath Simmons, PhD

Patient-Provider Disconnect In-depth interviews with 20 patients with lung and head and neck cancer and 11 health-care providers2 “found a bit of a disconnect between patients and providers with regard to the type of risk information” being communicated, Dr. Simmons told The ASCO Post. “We found that patients reported that their providers may mention that there are some long-term risks associated with smoking, such as the chance of cancer recurrence, but the message that was not getting out was that there

somebody’s willingness to quit, and in terms of actually assisting in the quit attempt and arranging for some sort of follow-up, that is where things seemed to really fall off. So there is definitely a lot of room for improvement,” Dr. Simmons stated. “Overall, patients reported that physicians implemented the 5A’s to a greater degree than staff,” according to the study report. “Patients were more likely to report that physicians asked their smoking status, advised them to

ogy health-care providers were following Public Health Service guidelines to use the “5A’s” model of brief smoking cessation intervention: “(1) ask all patients whether they use tobacco, (2) advise all smokers to quit, (3) assess smokers’ willingness to quit, (4) assist smokers with quitting, and (5) arrange follow-up contact to prevent relapse.”3 “We found that providers were doing a good job in terms of asking about tobacco use, and advising smokers to quit. However, only half were assessing

quit, and assisted them in quitting by writing them a prescription,” the report continued.

Provider’s Role “In speaking to providers, one of the issues was that they feel that they are not prepared, that it is somebody else’s role, perhaps, to deal with the smoking,” Dr. Simmons continued. “There is definitely a need for more research in this area, because we did find a lot of variability in terms of how providers talked about

smoking with their patients. Some providers were very sensitive to the stigma that cancer patients may feel with regard to their smoking, and others may not have as much sensitivity as needed for that topic.” Dr. Brandon, who serves on the American Association for Cancer Research Tobacco and Cancer Subcommittee, said, “We are working on a policy statement right now regarding the importance of assessing and treating tobacco dependence in patients with cancer.” He said that he expects that statement to be published within the next few months. n References 1. Simmons VN, Litvin EB, Jacobsen PB, et al: Predictors of smoking relapse in patients with thoracic cancer or head and neck cancer. Cancer. December 20, 2012 (early release online). 2. Simmons, VN, Litvin EB, Patel RD, et al: Patient-provider communication and perspectives on smoking cessation and relapse in the oncology setting. Patient Educ Couns 77:398-403, 2009. 3. Simmons, VN, Litvin EB, Unrod M, Brandon TH: Oncology healthcare providers’ implementation of the 5A’s model of brief intervention for smoking cessation: Patients’ perceptions. Patient Educ Couns 86:414-419, 2012.

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depending on presurgery smoking status. At 12 months after surgery, 60% of patients who smoked during the week prior to surgery had resumed smoking vs only 13% of patients who were abstinent prior to surgery. Notably, these relapse rates are lower than among smokers in the general population (95%), likely reflecting the high level of motivation and interest in smoking cessation expressed by patients with cancer,” according to the study report.

Predictors of Smoking Relapse The study found several variables (measured at baseline) that were predictors of smoking relapse. Among patients who quit smoking before surgery, the two significant factors predicting relapse were higher perceived difficulty quitting and lower perceived links between smoking and cancer. Among patients still smoking before surgery, significant predictors of relapse were “higher depression proneness,” greater fears about cancer recurrence, and lower expectations about being able to quit (self-efficacy for quitting). “Anytime that you are working with individuals who are quitting smoking, it is important to assess for depression and consider treatments for depression,” Dr. Simmons said. Dr. Brandon added, “Depression and smoking are often comorbid. Smokers are twice as likely as nonsmokers to have a history of depression and vice versa. Some of these people have been treated for depression or need formal treatments for depression, while some just need to learn other skills to replace smoking as their main mood control mechanism.” For smokers trying to quit, nicotine withdrawal can cause more depressed moods. Those moods generally improve in about 2 to 3 weeks, although that varies by individual, Dr. Brandon noted. “In the long run, people are generally less depressed after they quit smoking,” he said. Greater fear of cancer recurrence “was an interesting variable for us to measure because we didn’t know how it was going to play out,” Dr. Simmons said. “If somebody has a fear of their cancer recurring, might that protect them in terms of making them less likely to smoke, or might it cause more anxiety or depression, which we know is strongly related to smoking? And that second possibility is actually the way that the results came out.” Interventions for these people should directly address their fear, neg-

ative mood, and relationship to smoking. “We talk to them about alternative ways (other than smoking) to deal with negative mood and fears or anxieties they have about their cancer,” Dr. Simmons explained. “The construct of self-efficacy in smoking is one that has been well studied, even outside of the cancer population,” Dr. Simmons noted. “We know that individuals with lower selfefficacy or confidence in their quitting

“When you get a cancer diagnosis, it is a shocking experience and you may have these great intentions to quit smoking and may even be able to quit smoking for a while,” Dr. Brandon said. “What we know less about are the long-term outcomes of these attempts, once patients habituate to the idea that they have cancer, and especially if they are being successfully treated—do they maintain that same motivation to quit smoking?”

Anytime that you are working with individuals who are quitting smoking, it is important to assess for depression and consider treatments for depression. —Vani Nath Simmons, PhD

are more likely to resume smoking,” she explained. The results reported in the current study “support the need for relapse prevention interventions that address quitting self-efficacy,” the investigators wrote. “Testimonials from cancer patients who have long histories of smoking and have successfully maintained their abstinence after cancer treatment may prove effective.”

Relapse Prevention Trial “Based on the results of this study, we are now running a clinical trial that is testing a smoking relapse intervention and in fact uses patient testimonials as one way to enhance selfefficacy,” Dr. Simmons said. These testimonials are included on a DVD that patients in the intervention arm of the trial receive while they are still in the hospital, along with a self-help booklet. Then over the course of the first 3 months after they’ve left the hospital, patients receive the remaining seven booklets in the series. Patients randomized to the usual care arm would have access to the smoking cessation and relapse prevention services offered to all patients at Moffitt identified as smokers. “Because this was a longitudinal study, we were able to look at the trajectories of relapse over time and found that the high-risk period where most of the relapse occurred was in the first 2 months,” Dr. Simmons said. “This would really suggest, consistent with literature already published, that some sort of contact or intervention needs to occur even after individuals leave the hospital setting. Certainly once symptoms start to dissipate and patients start to feel better, their risk of relapse may increase,” she noted.

He continued, “It reminds me of another area of our research, which is smoking cessation in pregnant women. Many pregnant women will quit smoking when they become pregnant—not enough, but more than in the general population. They are very motivated at that point, but almost all of them relapse after they deliver the baby, despite the risk of secondhand smoke to the baby. There is a short-term motivation, but that may not persist for the long term.”

The self-help booklets are from the Forever Free series developed under the leadership of Dr. Brandon and “shown to be effective in two clinical trials, as well as very cost-effective,” Dr. Simmons said. “Our thinking behind the intervention was to take something that has already been demonstrated to be effective in reducing relapse among the general population and combine that with more targeted information specifically for cancer patients, which we have done through the DVD format.” The Forever Free booklets are posted on the National Cancer Institute website at www. smokefree.gov. “This is a relatively inexpensive and highly disseminable type of intervention,” Dr. Brandon noted. “If it is validated in the clinical trial, it is something that could be used by cancer centers or other hospitals around the country.” n

Disclosure: Drs. Simmons and Brandon reported no potential conflicts of interest.

Reference 1. Simmons VN, Litvin EB, Jacobsen PB, et al: Predictors of smoking relapse in patients with thoracic cancer or head and neck cancer. Cancer. December 20, 2012 (early release online).

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Emerging Clinical Data on Cancer Management MELANOMA Trametinib Shows Activity in Previously Treated but BRAF Inhibitor–naive BRAF-mutant Melanoma In a multicenter phase II study, trametinib showed “significant clinical activity” in a cohort of BRAF inhibitor–naive patients with BRAF-mutant cutaneous melanoma previously treated with chemotherapy and/or immunotherapy. Only minimal clinical activity, however, was observed among a cohort of patients who had previously been treated with a BRAF inhibitor. Results were published in the Journal of Clinical Oncology. All patients in the trial received 2 mg of the MEK1/MEK2 inhibitor trametinib orally once daily. The median time for receiving the study drug was 56 days for those previously treated with a BRAF inhibitor (dabrafenib or vemurafenib [Zelboraf]) and 120 days for those previously treated with chemotherapy and/or immunotherapy. Among the 40 patients who had previously been treated with a BRAF inhibitor, none had confirmed objective responses and 11 (28%) had stable disease. The median progression-free survival was 1.8 months. The researchers concluded that these data suggest that “BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy.” Among the 57 patients who had not previously been treated with a BRAF inhibitor, the confirmed response rate was 25%. One patient (2%) had a complete response, and 13 patients (23%) had partial responses. In addition, 29 patients (51%) had stable disease. The median progression-free survival was 4.0 months. “Activity was broad,” the researchers noted, with objective responses observed in patients with BRAF V600E and V600K (the more common BRAF mutations), as well as rare BRAF mutations. “These data support further evaluation of trametinib in BRAF inhibitor–naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma,” the investigators stated. They also noted that trametinib monotherapy could be useful for patients who cannot tolerate a BRAF inhibitor. “The most frequent treatmentrelated adverse events for all patients were skin-related toxicity, nausea,

peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed,” the researchers reported. No treatmentrelated deaths occurred, and only one grade 4 adverse event, which was pulmonary embolism.

Kim KB, et al: J Clin Oncol 31:482-489, 2013.

OVARIAN CANCER Short-term Survival Advantage of Carrying BRCA Mutation Does Not Extend to Long Term While carrying a BRCA 1 or BRCA 2 mutation was associated with a better prognosis in the 3-year period after diagnosis of invasive ovarian cancer, this short-term survival advantage did not lead to long-term survival benefit, according to a study published in the Journal of the National Cancer Institute. The study followed 1,626 unselected women diagnosed with invasive ovarian cancer in Ontario, Canada, and Tampa, Florida, for a mean of 6.9 years (range, 0.3–15.7 years). Among these women, “129 were identified as carriers of BRCA1 mutations, 89 were identified as carriers of BRCA2 mutations, and 1,408 were classified as noncarriers,” the researchers reported. Overall, the mutation carriers made up 13.4% of the study population. “The mutation carriers had an unfavorable distribution of stage, grade, and histology, compared with noncarriers and therefore an adjusted analysis was conducted,” the researchers reported. “In multivariable survival analysis, adjusted for histologic subtype, age at diagnosis, disease stage, and grade, the presence of a BRCA1 or BRCA2 mutation was associated with a better prognosis at 3 years after diagnosis (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.48– 0.98; P = .03). The advantage waned over time; at 5 years after diagnosis, the hazard ratio was 0.79 (95% CI = �� .06), and at 10 years af0.63–1.01; P =�� ter diagnosis, the hazard ratio was 1.00 (95% CI = 0.83–1.22; P = .90).» Women with serous cancers (73% of the BRCA mutation carriers and 53% of the nonhereditary cases) had worse survival than women with other histologic subtypes. Among women with serous cancers, 12-year survival (which the investigators deemed “a reasonable surrogate for cure”) was

similar for BRCA1 mutation carriers (27.4%), BRCA2 mutation carriers (27.7%), and noncarriers (27.1%). “We believe that there is insufficient evidence to conclude that survival from ovarian cancer differs between carriers and noncarriers, and we disagree with the recommendation that health-care providers should counsel women with ovarian cancer and carrying BRCA mutations that they should expect their survival to be better than that of noncarriers or that treatment could be tailored to reflect the differences in survival,” the authors concluded. McLaughlin JR, et al: J Natl Cancer Instit 105:141-148, 2013.

LEUKEMIA/LYMPHOMA Older Patients Do Better with Hematopoietic Transplants from Siblings of Similar Age than from Younger but Unrelated Donors Patients ≥�� 50 years old with leukemia/lymphoma are increasingly undergoing allogeneic hematopoietic cell transplants, raising questions about whether they might have better outcomes with transplants from younger allele-level 8/8 human leukocyte antigen (HLA)-matched unrelated donors than from HLA-matched siblings, who tend to be nearly as older than the patients themselves. “For older-age patients, use of a sibling donor, who usually is of a similar age to the patient, can be problematic due to the common presence of comorbidities as well as concerns regarding the regenerative potential of stem and immune cells from older donors,” noted authors of a study, published in the journal Blood, comparing outcomes for patients ≥ 50 who received hematopoietic cell transplants from matched sibling or matched unrelated donors. A total of 1,415 patients received transplants from their siblings (median age 58, range 50-85 years) and 757 patients received transplants from unrelated donors (median age 34, range 19-49 years). The risks of acute and chronic graft-vs-host disease (GVHD) were higher after transplants from unrelated than from sibling donors. “The day-100 probability of acute grade 2-4 GVHD was higher at 46% (95% confidence interval [CI] = 43–50) after matched unrelated donor transplantation compared to 38% (95% CI

= 35–40) after [matched sibling donor] transplantation (P < .001). The corresponding probabilities of acute grade 3-4 GVHD were 29% (95% CI = 26–32) after [matched unrelated donor] transplantation compared to 21% (95% CI = 19–23) after [matched sibling donor] transplantation (P < .001),” the investigators reported. The 3-year probabilities of chronic graft-vs-host disease were 51% (95% CI = 46%–56%) after matched unrelated donor transplantation compared to 47% (95% CI = 43%–50%) after matched sibling donor transplantation (P = .12), the authors added. Multivariate analysis showed that chronic graft-vs-host disease was higher after matched unrelated donor transplantation compared to matched sibling donor transplantation, after adjusting for other significant factors associated with chronic graft-vs-host disease. Performance scores affected risks of nonrelapse mortality and overall mortality. These risks were higher among patients with scores of 90 to 100 who received transplants from nonrelated than from matched sibling donors, but the risks were not significantly different for patients with lower performance scores. Relapse risks were also higher for those transplanted in relapse vs those in remission, and those who received reduced intensity compared to myeloablative regimens. Mortality, treatment failure, and relapse risks were lower for patients with chronic lymphocytic leukemia, compared to acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and non-Hodgkin lymphoma. “As patient age is correlated with donor age in the group of patients who received [matched sibling donor] transplants, we explored for a donor age cut-off in this population; after adjusting for performance score, conditioning regimen, disease, and disease status, overall mortality risks were higher in patients who received grafts from their siblings aged 67 years or older compared to those who received grafts from siblings aged 50–66 years [hazard ratio (HR) = 1.47, 95% CI = 1.19–.82, P < .001],” the investigators reported. “Relapse risks but not [graftvs-host disease or nonrelapse mortality] were also higher in patients who continued on page 124

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Emerging Clinical Data on Cancer Management continued from page 123

received grafts from their siblings aged 67 years or older compared to those who received grafts from younger siblings [HR = 1.55, 95% CI = 1.18–2.05, P = .002]. Among unrelated donors we did not identify an age cut-point

associated with survival,” the authors noted. They concluded: “When selecting a donor for patients who are 50 years or older with performance scores of 90 or 100, priority should be for a sibling donor aged less than 67 years than a younger-aged [matched unrelated donor]. Similarly, for patients with lower

performance scores and/or when the donor is 67 years or older,” lower acute and chronic graft-vs-host-disease rates after matched sibling donor compared to matched unrelated donor transplantation favor a matched sibling donor when available.

Alousi AM, et al: Blood, January 29, 2013 (early release online).

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• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Cervical Cancer NCCN Guidelines® Insights: Non-Hodgkin’s Lymphomas In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• Optimizing Neoadjuvant Therapy for Rectal Cancer With Oxaliplatin • Cutaneous T-Cell Lymphoma in Sub-Saharan Africa • Maintenance Therapy With Tyrosine Kinase Inhibitors After Transplant in Patients With Chronic Myeloid Leukemia • What is the Appropriate Approach to Treating Women With Incurable Cervical Cancer?

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Short Wait for Lab Results Is Reasonable Strategy to Better Characterize AML and Design Therapy Waiting a short period of time for laboratory results to better characterize acute myeloid leukemia (AML) and design therapeutic approaches is a reasonable strategy, researchers in Toulouse, France, found after a retrospective review of 599 newly diagnosed AML patients treated by induction chemotherapy. The researchers studied the impact of time from diagnosis to treatment on overall survival, early death, and response rate and reported their results in the journal Blood. Other factors considered were pretreatment characteristics at diagnosis (such as age, gender, Eastern Cooperative Oncology Group (ECOG) performance status, and secondary AML) and white blood cell (WBC) and platelet counts. In multivariate analysis, time from diagnosis to treatment had no impact on overall survival (P = .4095) as compared to age older than 60, secondary AML, white blood cell count higher than 50 g/L, European LeukemiaNet risk groups, and ECOG performance status. Moreover, time from diagnosis to treatment was not associated with response rate or early death, the researchers reported The investigators noted that AML is very heterogeneous and while the morphologic diagnosis of AML can be done in a few hours, the results of cytogenetic tests can take a week or longer. “Thus, there is a dilemma between the potential benefit of genetically targeted therapy early at diagnosis and the risk of delaying the initiation of chemotherapy,” the authors stated. “This fear has been recently addressed by two North American centers in a retrospective study showing that the time from diagnosis to treatment independently predicted survival in younger but not older patients,” the researchers wrote. In that study by Sekeres et al (Blood 113:28-36, 2009), response rate and overall survival worsened after a treatment delay of 5 days. “On the basis of these results,” the current investigators noted, “it is commonly admitted that treatment of younger AML patients should be started with minimal delay.” Acknowledging that their results differ, the French researchers noted that they found much less secondary AML (20% vs 45%) in both younger and older patients. “The other main

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difference resides in the chemotherapy regimen,” the investigators stated. “For induction therapy, we have invariably used daunorubicin (180 mg/m2) or idarubicin (40 mg/m2) in combination with standard-dose cytarabine. In contrast, induction chemotherapies were variable in the Sekeres study with several modalities of cytarabine administration, compounds other than anthracyclines (such as topotecan, cyclophosphamide, or clofarabine) used in combination with cytarabine, and no description of the dose of daunorubicin, which is crucial for complete response and overall survival. Lastly, we have no information on the modalities of consolidation therapies and the proportion of patients receiving allogeneic stem-cell transplantation,” the researchers added. “It is unlikely that a randomized trial addressing the effect of [time from diagnosis to treatment] would be undertaken. Therefore, studies from other centers relating their own experience are needed,” the researchers concluded. “Since personalized therapies based on genetic features of AML are going to be developed, it is fundamental to have a clear vision of the impact of [time from diagnosis to treatment] on the outcome of AML patients. Although AML remains an oncologic emergency, our study suggests that, except for specific conditions, it does not seem unreasonable to wait for specialized laboratory tests in order to better characterize leukemias and design new therapeutic strategies.”

Bertoli S, et al: Blood, January 30, 2013 (early release online).

RENAL CELL CARCINOMA PET/CT With 124I-Girentuximab Can Identify Clear Cell Renal Cell Carcinoma While Minimizing Invasive Diagnostic Risks Positron-emission tomography/ computed tomography (PET/CT) with iodine-124 (124I) –girentuximab “can accurately and noninvasively identify” clear cell renal cell carcinoma, according to a phase III multicenter study reported in the Journal of Clinical Oncology. In addition, “PET/ CT with 124I-girentuximab may be of value in risk stratification of patients with renal masses, and it fulfills an unmet medical need to improve appropriate patient care while minimizing the risks of invasive diagnostics and

potentially unnecessary surgery,” the investigators concluded. PET/CT and contrast-enhanced CT of the abdomen were performed on patients 2 to 6 days after intravenous 124I-girentuximab administration and before resection of renal masses. Among 195 patients with complete data sets (histopathologic diagnosis and PET/CT and contrast-enhanced CT results) available, the average sensitivity was 86.2% for PET/CT and 75.5% for contrast-enhanced CT (P = .023). The average specificity was 85.9% for PET/CT and 46.8% for contrast-enhanced CT (P = .005). “124I-girentuximab was well tolerated. There was no evidence of allergic reaction or drug intolerance,” the investigators stated. “This multicenter trial demonstrated that 124I-girentuximab PET/ CT could provide information on the presence or absence of [clear cell renal cell carcinoma] with accuracy at least comparable to that of biopsy, while obviating the need for this procedure with its inherent risks,” the authors asserted. In addition, 124Igirentuximab PET/CT “may play an important role in surgical planning by improving tumor characterization in patients with unilateral multicentric or bilateral lesions,” the authors stated. “These data suggest,” the researchers pointed out, “ that patients presenting with incidentally identified T1 renal masses may benefit from the incorporation of 124I-girentuximab PET/ CT to optimally inform a clinical management decision and add confidence and clarity to rational therapeutic recommendations for the surgically fragile, elderly, or comorbidly ill patient.” Divgi CR, et al: J Clin Oncol 31:187194, 2013.

113,752 women and 88,496 men 25 years of age or older interviewed between 1997 and 2004 in the U.S. National Health Interview Survey and related these data to causes of deaths that occurred in 8,236 women and 7,479 men by December 31, 2006. For participants who were 25 to 79 years of age, the rate of death from any cause among current smokers was about three times that among those who had never smoked. “Most of the excess mortality among smokers was due to neoplastic, vascular, respiratory, and other diseases that can be caused by smoking,” the researchers reported. “The probability of surviving from 25 to 79 years of age was about twice as great in those who had never smoked as in current smokers (70% vs 38% among women and 61% vs 26% among men). Life expectancy was shortened by more than 10 years among the current smokers, as compared with those who had never smoked,” they added. “Adults who had quit smoking at 25 to 34, 35 to 44, or 45 to 54 years of age gained about 10, 9, and 6 years of life, respectively, as compared with those who continued to smoke,” the researchers reported. They noted, “the women in this cohort represent the first generation of women in the United States in which those who smoked began early in life and smoked for decades, and the risks of death for these women are about 50% greater than the risks reported in the 1980s studies.”

Second Study That finding was corroborated by the other study, which measured 50year trends in smoking-related mortality in the United States, and found that for women who were current smok-

ers, compared to women who never smoked, the relative risks of death from lung cancer increased from 12.65 in the 1980s to 25.66 in the period from 2000 to 2010. The corresponding relative risk for males was almost the same—24.97. Current male and female smokers “also had similar relative risks for death from chronic obstructive pulmonary disease (25.61 for men and 22.35 for women), ischemic heart disease (2.50 for men and 2.86 for women), any type of stroke (1.92 for men and 2.10 for women), and all causes combined (2.80 for men and 2.76 for women),” according to the study. “Among men 55 to 74 years of age and women 60 to 74 years of age, all-cause mortality was at least three times as high among current smokers as among those who had never smoked,” the study report continued. Both reports stress the importance of smoking cessation efforts. “Our analyses of data from former smokers confirm that quitting smoking at any age dramatically lowers mortality from all major smoking-related diseases,” according to the analysis of 50-year trends in smoking-related mortality. Moreover, “nearly all the excess risk can be avoided if a person quits smoking before 40 years of age,” the authors pointed out. “A focus on cessation of smoking is justified, since quitting smoking before the age of 40 years, and preferably much earlier, will reduce by about 90% the decade of life that is lost from continued smoking,” asserted the authors of the other study. n Jha P, et al: N Engl J Med. January 24, 2013 (early release online). Thun MJ, et al: N Engl J Med. January 24, 2013 (early release online).

SMOKING Large Epidemiologic Studies Re-examine Hazards of Smoking “Smokers lose at least one decade of life expectancy, as compared with those who have never smoked,” and the increased risk of death from cigarettes smoking “are now nearly identical for men and women,” according to two separate studies published online by The New England Journal of Medicine. One study looked at smoking and smoking-cessation histories from

T:10.25" S:9.5" PAGE 126

The ASCO Post | MARCH 15, 2013

News Health-care Policy

Sequestration Will Have Shattering Impact on Entire U.S. Cancer Enterprise

Statement by ASCO President Sandra M. Swain, MD, FACP American Society of Clinical Oncology

arch 1 marked the beginning of sequestration, the unprecedented automatic budget cuts that immediately take effect across the federal government—after months of futile negotiations by the President and Congress. Sequestration will have a shattering impact on the entire cancer enterprise in the United States. The cuts will be far-reaching and widely felt, and—ultimately—it’s the cancer patient, fighting for his or her life, who’s going to feel

major cancer-related activities now must implement the sequestrationmandated, across-the-board budget reductions. Posing a triple threat to cancer patients, the budgets of the National Institutes of Health and the Food and Drug Administration will be reduced by more than 5% each, and Medicare reimbursement to physicians who provide cancer care will be reduced by 2%. ASCO is deeply disappointed in the failure of lawmakers to avert this fiscal

ASCO will immediately urge Congress to enact measures that retroactively reinstate critical funding to ensure patients have continued access to high quality cancer care. —Sandra M. Swain, MD, FACP

the most profound impact from reductions in clinical cancer research, slowdowns in the drug review and approval process, and oncology practices being squeezed by cuts to reimbursement. With the White House and Congress unable to reach a bipartisan agreement, federal agencies that fund

crisis, and will closely monitor the impact of sequestration on the oncology community. In the meantime, ASCO will immediately urge Congress to enact measures that retroactively reinstate critical funding to ensure patients have continued access to high quality cancer care. n

Send Us Your OP-ED Write to editor@ASCOPost.com. All submissions will be considered for publication.

AVASTIN® (bevacizumab)

Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information.

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin in combination with fluoropyrimidine‑irinotecan or fluoropyrimidine‑ oxaliplatin based chemotherapy is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).] 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL.

T:10.25" S:9.5" AVASTIN® (bevacizumab)

AVASTIN® (bevacizumab)

Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

(approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm. Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks.

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage

8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence ( ≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥65 years (8.5% vs. 2.9%) as compared to those <65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

S:12.5"

Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). [See Warnings and Precautions (5.8).]

Arm 2 IFL+ + Avastin (n = 392) 87%

T:13" S:12.5"

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

Arm 1 IFL+ + Placebo (n = 396) 74%

8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.

NOW APPROVED: Avastin continued beyond first progression in MCRC In combination with fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival The only biologic to prospectively demonstrate significant overall survival (OS) in a Phase III MCRC trial after treatment with a first-line Avastin-containing regimen1 Median OS:

Percentage Surviving

100

11.2 vs 9.8 months

(HR=0.81 [95% CI, 0.69–0.94], P=0.0057)

80 60

Avastin + fluoropyrimidine-based chemotherapy* (n=409) Fluoropyrimidine-based chemotherapy* alone (n=411)

40 20 0

24 OS (Months)

*Chemotherapy combinations included both irinotecan- and oxaliplatin-containing regimens. At first progression, chemotherapy was switched: oxaliplatin→irinotecan or irinotecan→oxaliplatin.1

1.7-month increase in median PFS beyond first progression with Avastin plus fluoropyrimidine-based chemotherapy*: 5.7 vs 4.0 months with fluoropyrimidine-based chemotherapy* alone (HR=0.68 [95% CI, 0.59–0.78], P<0.0001)1 There was no significant difference in response rate1

MCRC=metastatic colorectal cancer; HR=hazard ratio; CI=confidence interval; PFS=progression-free survival.

Indications

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%)

AVA0001557000

Printed in USA.

Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across all studies, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

When continued beyond first progression in MCRC, no new safety signals were observed in Study ML18147 when Avastin was administered in second-line MCRC patients who progressed on an Avastin-containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information. Reference: 1. Avastin Prescribing Information. Genentech, Inc. January 2013.

(01/13)